Compounds, compositions, and methods

ABSTRACT

The present disclosure relates generally to LRRK2 inhibitors, or a pharmaceutically acceptable salt, deuterated analog, prodrug, tautomer, stereoisomer, or mixture of stereoisomers thereof, and methods of making and using thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 15/624,566filed Jun. 15, 2017, which application claims the benefit under 35U.S.C. § 119(e) to U.S. Provisional Application Nos. 62/350,876 filedJun. 16, 2016, 62/417,151 filed Nov. 3, 2016, 62/476,581 filed Mar. 24,2017, and 62/510,711 filed May 24, 2017, and all of which areincorporated by reference.

FIELD

The present disclosure relates generally to novel heteroaryl-substitutedpyrimidines and their use as therapeutic agents, for example, asinhibitors of LRRK2.

BACKGROUND

Neurodegenerative diseases, such as Parkinson's disease, amyotrophiclateral sclerosis (ALS), Alzheimer's disease, Lewy body dementia, andHuntington's disease affect millions of people. Parkinson's disease is achronic, progressive motor system disorder characterized by selectivedegeneration and cell death of dopaminergic neurons in the substantialnigra region of the brain. This leaves patients with impaired ability todirect and control their movements. The cause of the disease wasgenerally considered to be sporadic and unknown, but significantadvancements in understanding have been made in the last 15 years.

The genetic basis for the disease and associated pathogenic mechanismshave led exploration of the gene encoding leucine-rich repeat kinase 2(LRRK2) protein and its association with hereditary Parkinson's disease(Paisan-Ruiz et al., Neuron, Vol. 44(4), 2004, 601-607). LRRK2 is amember of the ROCO protein family and shares five conserved domains withall other family members. Many mis-sense mutations to the LRRK2 genehave been linked with autosomal dominant Parkinson's disease in familialstudies (Trinh and Farrar, Nature Reviews in Neurology, Vol. 9, 2013,445-454; Paisan-Ruiz et al., J. Parkinson's Disease, Vol. 3, 2013,85-103). The most common pathogenic mutation, G2019S, occurs in thehighly conserved kinase domain of LRRK2 (See Gilks et al., Lancet, Vol365, 2005, 415-416). In vitro studies indicate Parkinson'sdisease-associated mutation leads to increased LRRK2 activity and adecreased rate of GTP hydrolysis (Guo et al., Experimental CellResearch, Vol. 313(16), 2007, 3658-3670). This evidence suggests thekinase and GTPase activities of LRRK2 are important for pathogenesis andthe LRRK2 kinase domain may regulate overall LRRK2 function (SeeCookson, Nat. Rev. Neurosci., Vol. 11, 2010, 791-797).

While progress has been made in this field, there remains a need forimproved inhibitors of the LRRK2 receptor which are useful for treatmentof various neurodegenerative diseases, such as Parkinson's disease,Alzheimer's disease and amyotrophic lateral sclerosis.

DESCRIPTION

Provided herein are compounds that are useful as inhibitors of LRRK2.The disclosure also provides compositions, including pharmaceuticalcompositions, kits that include the compounds, and methods of using (oradministering) and making the compounds. The disclosure further providescompounds or compositions thereof for use in a method of treating adisease, disorder, or condition that is mediated, at least in part, byLRRK2. Moreover, the disclosure provides uses of the compounds orcompositions thereof in the manufacture of a medicament for thetreatment of a disease, disorder, or condition that is mediated, atleast in part, by LRRK2.

In one embodiment, provided is a compound of formula I:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R¹ is optionally substituted cycloalkyl or, when R⁵ is —CR^(5a)R⁶R⁷where R^(5a) is optionally substituted triazol-2-yl, R¹ is optionallysubstituted cycloalkyl or C₁₋₆ alkyl optionally substituted with halo;

R² is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²);

R³ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R¹¹)(R¹²);

R⁴ is hydrogen or halo;

R⁵ is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²);

R⁶ and R⁷ are each independently H or optionally substituted C₁₋₆ alkyl;

each R¹⁰ is independently optionally substituted C₁₋₆ alkyl oroptionally substituted C₁₋₆ alkoxy; and

R¹¹ and R¹² are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R¹¹ and R¹² together forman optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula II:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R²⁰ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R²³;

R²¹ is optionally substituted cycloalkyl, heteroaryl, C₁₋₆ alkoxy,—S—C₁₋₆ alkyl, or —N(R²⁴)(R²⁵);

m is 0, 1, 2, 3, or 4;

each R²² is independently halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ aminoalkyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkylheteroarylalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl,amido, amidoalkyl, or —C(O)R²⁶, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ aminoalkyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylalkyl, cycloalkyl,cyanocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkylheteroarylalkyl, heteroarylcycloalkyl, andalkylheteroarylcycloalkyl is optionally substituted; or

two R²² together with the atom to which they are attached form acycloalkyl or heterocyclyl, wherein each cycloalkyl and heterocyclyl isoptionally substituted;

R²³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R²⁷)₂, or heterocyclyl, wherein eachC₁₋₆ alkyl, C₁₋₆ alkoxy and heterocyclyl is optionally substituted;

R²⁴ and R²⁵ are each independently hydrogen or optionally substitutedC₁₋₆ alkyl; or

R²⁴ and R²⁵ together with the atom to which they are attached form anoptionally substituted heterocyclyl;

R²⁶ is C₁₋₆ alkyl or heterocyclyl, wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl,and heterocyclyl is independently optionally substituted with one ormore substituents selected from halo, cyano, hydroxy, C₁₋₆ alkoxy, andC₁₋₆ alkylsulfonyl;

each R²⁷ is independently H or optionally substituted C₁₋₆ alkyl;

and A is a heterocyclyl or heteroaryl ring fused to the pyrazole.

In some embodiments, the compound is in Table 1A, 1B, 2A or 2B, or is apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof.

In another embodiment, provided is a pharmaceutical compositioncomprising a compound as shown in Table 1A, 1B, 2A or 2B, or apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, provided is a method for treating a disease orcondition mediated, at least in part, by LRRK2, the method comprisingadministering an effective amount of the pharmaceutical compositioncomprising a compound as shown in Table 1A or Table 1B, or apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof, and apharmaceutically acceptable carrier, diluent, or excipient, to a subjectin need thereof.

In another embodiment, provided is a pharmaceutical compositioncomprising a compound as shown in Table 1A or Table 1B, or apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof, and apharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, provided is a method for treating a disease orcondition mediated, at least in part, by LRRK2, the method comprisingadministering an effective amount of the pharmaceutical compositioncomprising a compound as shown in Table 1A or Table 1B, or apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof, and apharmaceutically acceptable carrier, diluent, or excipient, to a subjectin need thereof. In another embodiment, provided is a method fortreating a disease or condition mediated, at least in part, by LRRK2,the method comprising administering an effective amount of thepharmaceutical composition comprising a compound as shown in Table 1A,1B, 2A or 2B, or a pharmaceutically acceptable salt, deuterated analog,prodrug, tautomer, stereoisomer, or a mixture of stereoisomers thereof,and a pharmaceutically acceptable carrier, diluent, or excipient, to asubject in need thereof.

The description herein sets forth exemplary embodiments of the presenttechnology. It should be recognized, however, that such description isnot intended as a limitation on the scope of the present disclosure butis instead provided as a description of exemplary embodiments.

1. Definitions

As used in the present specification, the following words, phrases andsymbols are generally intended to have the meanings as set forth below,except to the extent that the context in which they are used indicatesotherwise.

A dash (“—”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line or a dashed line drawn through a line in astructure indicates a specified point of attachment of a group. Unlesschemically or structurally required, no directionality orstereochemistry is indicated or implied by the order in which a chemicalgroup is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl) or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.—(CH₂)₃CH₃), sec-butyl (i.e. —CH(CH₃)CH₂CH₃), isobutyl (i.e.—CH₂CH(CH₃)₂) and tert-butyl (i.e. —C(CH₃)₃); and “propyl” includesn-propyl (i.e. —(CH₂)₂CH₃) and isopropyl (i.e. —CH(CH₃)₂).

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.arylalkyl or aralkyl, the last mentioned group contains the atom bywhich the moiety is attached to the rest of the molecule.

“Alkenyl” refers to an alkyl group containing at least one carbon-carbondouble bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkenyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkenyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkenyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkenyl). Examples ofalkenyl groups include ethenyl, propenyl, butadienyl (including1,2-butadienyl and 1,3-butadienyl).

“Alkynyl” refers to an alkyl group containing at least one carbon-carbontriple bond and having from 2 to 20 carbon atoms (i.e., C₂₋₂₀ alkynyl),2 to 8 carbon atoms (i.e., C₂₋₈ alkynyl), 2 to 6 carbon atoms (i.e.,C₂₋₆ alkynyl) or 2 to 4 carbon atoms (i.e., C₂₋₄ alkynyl). The term“alkynyl” also includes those groups having one triple bond and onedouble bond.

“Alkoxy” refers to the group “alkyl-O—”. Examples of alkoxy groupsinclude methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

“Alkoxyalkyl” refers to the group “alkyl-O-alkyl”.

“Alkylthio” refers to the group “alkyl-S—”.

“Alkylsulfinyl” refers to the group “alkyl-S(O)—”.

“Alkylsulfonyl” refers to the group “alkyl-S(O)₂—”.

“Alkylsulfonylalkyl” refers to -alkyl-S(O)₂-alkyl.

“Acyl” refers to a group —C(O)R^(y), wherein R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethyl-carbonyl and benzoyl.

“Amido” refers to both a “C-amido” group which refers to the group—C(O)NR^(y)R^(z) and an “N-amido” group which refers to the group—NR^(y)C(O)R^(z), wherein R^(y) and R^(z) are independently hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein, or R^(y) and R^(z) are taken together to form a cycloalkyl orheterocyclyl; each of which may be optionally substituted, as definedherein.

“Amidoalkyl” refers to an alkyl group as defined above, wherein one ormore hydrogen atoms are replaced by an amido group.

“Amino” refers to the group —NR^(y)R^(z) wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aminoalkyl” refers to the group “-alkyl-NR^(y)R^(z),” wherein R^(y) andR^(z) are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Amidino” refers to —C(NR^(y))(NR^(z) ₂), wherein R^(y) and R^(z) areindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Aryl” refers to an aromatic carbocyclic group having a single ring(e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic)including fused systems. As used herein, aryl has 6 to 20 ring carbonatoms (i.e., C₆₋₂₀ aryl), 6 to 12 carbon ring atoms (i.e., C₆₋₁₂ aryl),or 6 to 10 carbon ring atoms (i.e., C₆₋₁₀ aryl). Examples of aryl groupsinclude phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does notencompass or overlap in any way with heteroaryl defined below. If one ormore aryl groups are fused with a heteroaryl, the resulting ring systemis heteroaryl. If one or more aryl groups are fused with a heterocyclyl,the resulting ring system is heterocyclyl.

“Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”.

“Carbamoyl” refers to both an “O-carbamoyl” group which refers to thegroup —O—C(O)NR^(y)R^(z) and an “N-carbamoyl” group which refers to thegroup —NR^(y)C(O)OR^(z), wherein R^(y) and R^(z) are independentlyhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein.

“Carboxyl ester” or “ester” refer to both —OC(O)OR^(x) and —C(O)OR^(x),wherein R^(x) is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,aryl, heteroalkyl, or heteroaryl; each of which may be optionallysubstituted, as defined herein.

“Cyanoalkyl” refers to refers to an alkyl group as defined above,wherein one or more hydrogen atoms are replaced by a cyano group.

“Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkylgroup having a single ring or multiple rings including fused, bridgedand spiro ring systems. The term “cycloalkyl” includes cycloalkenylgroups (i.e. the cyclic group having at least one double bond) andcarbocyclic fused ring systems having at least one sp³ carbon atom(i.e., at least one non-aromatic ring). As used herein, cycloalkyl hasfrom 3 to 20 ring carbon atoms (i.e., C₃₋₂₀ cycloalkyl), 3 to 12 ringcarbon atoms (i.e., C₃₋₁₂ cycloalkyl), 3 to 10 ring carbon atoms (i.e.,C₃₋₁₀ cycloalkyl), 3 to 8 ring carbon atoms (i.e., C₃₋₈ cycloalkyl), or3 to 6 ring carbon atoms (i.e., C₃₋₆ cycloalkyl). Monocyclic groupsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl. Polycyclic groups include, for example,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, adamantyl, norbornyl,decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further,the term cycloalkyl is intended to encompass any non-aromatic ring whichmay be fused to an aryl ring, regardless of the attachment to theremainder of the molecule. Still further, cycloalkyl also includes“spirocycloalkyl” when there are two positions for substitution on thesame carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, orspiro[5.5]undecanyl.

“Cycloalkoxy” refers to “—O-cycloalkyl.”

“Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-.”

“Cycloalkylalkoxy” refers to “—O-alkyl-cycloalkyl.”

“Guanidino” refers to —NR^(y)C(═NR^(z))(NR^(y)R^(z)), wherein each R^(y)and R^(z) are independently hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each ofwhich may be optionally substituted, as defined herein.

“Hydrazino” refers to —NHNH₂.

“Imino” refers to a group —C(NR^(y))R^(z), wherein R^(y) and R^(z) areeach independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Imido” refers to a group —C(O)NR^(y)C(O)R^(z), wherein R^(y) and R^(z)are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may beoptionally substituted, as defined herein.

“Halogen” or “halo” refers to atoms occupying group VIIA of the periodictable, such as fluoro, chloro, bromo, or iodo.

“Haloalkyl” refers to an unbranched or branched alkyl group as definedabove, wherein one or more hydrogen atoms are replaced by a halogen. Forexample, where a residue is substituted with more than one halogen, itmay be referred to by using a prefix corresponding to the number ofhalogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may be,but are not necessarily, the same halogen. Examples of haloalkyl includetrifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl and the like.

“Haloalkoxy” refers to an alkoxy group as defined above, wherein one ormore hydrogen atoms are replaced by a halogen.

“Hydroxyalkyl” refers to an alkyl group as defined above, wherein one ormore hydrogen atoms are replaced by a hydroxy group.

“Heteroalkyl” refers to an alkyl group in which one or more of thecarbon atoms (and any associated hydrogen atoms) are each independentlyreplaced with the same or different heteroatomic group, provided thepoint of attachment to the remainder of the molecule is through a carbonatom. The term “heteroalkyl” includes unbranched or branched saturatedchain having carbon and heteroatoms. By way of example, 1, 2, or 3carbon atoms may be independently replaced with the same or differentheteroatomic group. Heteroatomic groups include, but are not limited to,—NR^(y)—, —O—, —S—, —S(O)—, —S(O)₂—, and the like, wherein R^(y) ishydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl,heteroalkyl, or heteroaryl; each of which may be optionally substituted,as defined herein. Examples of heteroalkyl groups include ethers (e.g.,—CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂OCH₂CH₂OCH₃, etc.),thioethers (e.g., —CH₂SCH₃, —CH(CH₃)SCH₃, —CH₂CH₂SCH₃,—CH₂CH₂SCH₂CH₂SCH₃, etc.), sulfones (e.g., —CH₂S(O)₂C₃,—CH(CH₃)S(O)₂CH₃, —CH₂CH₂S(O)₂CH₃, —CH₂CH₂S(O)₂CH₂CH₂OCH₃, etc.), andamines (e.g., —CH₂NR^(y)CH₃, —CH(CH₃)NR^(y)CH₃, —CH₂CH₂NR^(y)CH₃,—CH₂CH₂NR^(y) CH₂CH₂NR^(y)CH₃, etc., where R^(y) is hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein). As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2heteroatoms, or 1 heteroatom.

“Heteroaryl” refers to an aromatic group having a single ring, multiplerings or multiple fused rings, with one or more ring heteroatomsindependently selected from nitrogen, oxygen and sulfur. As used herein,heteroaryl includes 1 to 20 ring carbon atoms (i.e., C₁₋₂₀ heteroaryl),3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heteroaryl), or 3 to 8 carbonring atoms (i.e., C₃₋₈ heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, oxygen and sulfur.In certain instances, heteroaryl includes 5-10 membered ring systems,5-7 membered ring systems, or 5-6 membered ring systems, eachindependently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1to 2 ring heteroatoms, or 1 ring heteroatom independently selected fromnitrogen, oxygen and sulfur. Examples of heteroaryl groups includeacridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl,benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl,benzothienyl (benzothiophenyl), benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl,indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl,oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl,1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl,pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl,quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl,tetrazolyl, and triazinyl. Examples of the fused-heteroaryl ringsinclude, but are not limited to, benzo[d]thiazolyl, quinolinyl,isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl,pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where theheteroaryl can be bound via either ring of the fused system. Anyaromatic ring, having a single or multiple fused rings, containing atleast one heteroatom, is considered a heteroaryl regardless of theattachment to the remainder of the molecule (i.e., through any one ofthe fused rings). Heteroaryl does not encompass or overlap with aryl asdefined above.

“Heteroarylalkyl” refers to the group “heteroaryl-alkyl-.”

“Heterocyclyl” refers to a saturated or partially unsaturated cyclicalkyl group, with one or more ring heteroatoms independently selectedfrom nitrogen, oxygen and sulfur. The term “heterocyclyl” includesheterocycloalkenyl groups (i.e. the heterocyclyl group having at leastone double bond), bridged-heterocyclyl groups, fused-heterocyclyl groupsand spiro-heterocyclyl groups. A heterocyclyl may be a single ring ormultiple rings wherein the multiple rings may be fused, bridged orspiro, and may comprise one or more oxo (═O) or N-oxide (—O⁻) moieties.Any non-aromatic ring containing at least one heteroatom is considered aheterocyclyl, regardless of the attachment (i.e., can be bound through acarbon atom or a heteroatom). Further, the term heterocyclyl is intendedto encompass any non-aromatic ring containing at least one heteroatom,which ring may be fused to an aryl or heteroaryl ring, regardless of theattachment to the remainder of the molecule. As used herein,heterocyclyl has 2 to 20 ring carbon atoms (i.e., C₂₋₂₀ heterocyclyl), 2to 12 ring carbon atoms (i.e., C₂₋₁₂ heterocyclyl), 2 to 10 ring carbonatoms (i.e., C₂₋₁₀ heterocyclyl), 2 to 8 ring carbon atoms (i.e., C₂₋₈heterocyclyl), 3 to 12 ring carbon atoms (i.e., C₃₋₁₂ heterocyclyl), 3to 8 ring carbon atoms (i.e., C₃₋₈ heterocyclyl), or 3 to 6 ring carbonatoms (i.e., C₃₋₆ heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1ring heteroatom independently selected from nitrogen, sulfur or oxygen.Examples of heterocyclyl groups include azetidinyl, azepinyl,benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl,benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl,dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl,indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl,phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl,pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl,thiophenyl (i.e. thienyl), tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl.The term “heterocyclyl” also includes “spiroheterocyclyl” when there aretwo positions for substitution on the same carbon atom. Examples of thespiro-heterocyclyl rings include bicyclic and tricyclic ring systems,such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl ringsinclude, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl,4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl,where the heterocyclyl can be bound via either ring of the fused system.

“Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-”.

The term “leaving group” refers to an atom or a group of atoms that isdisplaced in a chemical reaction as stable species taking with it thebonding electrons. The non-limiting examples of a leaving group include,halo, methanesulfonyloxy, p-toluenesulfonyloxy,trifluoromethanesulfonyloxy, nonafluorobutanesulfonyloxy,(4-bromo-benzene)sulfonyloxy, (4-nitro-benzene)sulfonyloxy,(2-nitro-benzene)-sulfonyloxy, (4-isopropyl-benzene)sulfonyloxy,(2,4,6-tri-isopropyl-benzene)-sulfonyloxy,(2,4,6-trimethyl-benzene)sulfonyloxy, (4-tert-butyl-benzene)sulfonyloxy,benzenesulfonyloxy, (4-methoxy-benzene)sulfonyloxy, and the like.

“Oxime” refers to the group —CR^(y)(═NOH) wherein R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein.

“Sulfonyl” refers to the group —S(O)₂R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl,phenylsulfonyl and toluenesulfonyl.

“Sulfinyl” refers to the group —S(O)R^(y), where R^(y) is hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, orheteroaryl; each of which may be optionally substituted, as definedherein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl,phenylsulfinyl and toluenesulfinyl.

“Sulfonamido” refers to the groups —SO₂NR^(y)R^(z) and —NR^(y)SO₂R^(z),where R^(y) and R^(z) are each independently hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;each of which may be optionally substituted, as defined herein.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen.

The term “substituted” used herein means any of the above groups (e.g.,alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) whereinat least one hydrogen atom is replaced by a bond to a non-hydrogen atomsuch as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio,acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl,carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanadino, halo,haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydrazine, hydrazone,imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl,alkylsulfonyl, alkylsulfinyl, thiocyanate, sulfinic acid, sulfonic acid,sulfonamido, thiol, thioxo, N-oxide, or —Si(R^(y))₃ wherein each R^(y)is independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl,cycloalkyl, aryl, heteroaryl, or heterocyclyl.

In one embodiment, “substituted” includes any of the above groups (e.g.,alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy,cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) in whichone or more hydrogen atoms are replaced with —NR^(g)R^(h),—NR^(g)C(═O)R^(h), —NR^(g)C(═O)NR^(g)R^(h), —NR^(g)C(═O)OR^(h),—NR^(g)SO₂R^(h), —OC(═O)NR^(g)R^(h), —OR^(g), —SR^(g), —SOR^(g),—SO₂R^(g), —OSO₂R^(g), —SO₂R^(g), ═NSO₂R^(g), and —SO₂NR^(g)R^(h).“Substituted” also means any of the above groups in which one or morehydrogen atoms are replaced with —C(═O)R^(g), —C(═O)OR^(g),—C(═O)NR^(g)R^(h), —CH₂SO₂R^(g), —CH₂SO₂NR^(g)R^(h). In the foregoing,R^(g) and R^(h) are the same or different and independently hydrogen,alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,and/or heteroarylalkyl. “Substituted” further means any of the abovegroups in which one or more hydrogen atoms are replaced by a bond to anamino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl,and/or heteroarylalkyl group. In addition, each of the foregoingsubstituents may also be optionally substituted with one or more of theabove substituents.

Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxy, halo,alkoxy, acyl, oxo, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl.In other embodiments, the one or more substituents may be furthersubstituted with halo, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl,heterocyclyl, aryl, or heteroaryl, each of which is substituted. Inother embodiments, the substituents may be further substituted withhalo, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclyl, aryl,or heteroaryl, each of which is unsubstituted.

Any compound or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted herein, exceptthat one or more atoms are replaced by an atom having a selected atomicmass or mass number. Examples of isotopes that can be incorporated intothe disclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C,¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³Cl, ¹²³I and¹²⁵I, respectively. Various isotopically labeled compounds of thepresent disclosure, for example those into which radioactive isotopessuch as ³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelledcompounds may be useful in metabolic studies, reaction kinetic studies,detection or imaging techniques, such as positron emission tomography(PET) or single-photon emission computed tomography (SPECT) includingdrug or substrate tissue distribution assays or in radioactive treatmentof patients.

The disclosure also includes “deuterated analogs” of compounds describedherein in which from 1 to n hydrogens attached to a carbon atom is/arereplaced by deuterium, in which n is the number of hydrogens in themolecule. Such compounds exhibit increased resistance to metabolism andare thus useful for increasing the half-life of any compound whenadministered to a mammal, particularly a human. See, for example,Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,”Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F, ³H, ¹¹C labeled compoundmay be useful for PET or SPECT or other imaging studies. Isotopicallylabeled compounds of this disclosure and prodrugs thereof can generallybe prepared by carrying out the procedures disclosed in the schemes orin the examples and preparations described below by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent. It is understood that deuterium in this context isregarded as a substituent in a compound described herein.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, stereoisomers and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, gluconic acid,glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid,ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid and thelike. Likewise, pharmaceutically acceptable base addition salts can beprepared from inorganic and organic bases. Salts derived from inorganicbases include, by way of example only, sodium, potassium, lithium,aluminum, ammonium, calcium and magnesium salts. Salts derived fromorganic bases include, but are not limited to, salts of primary,secondary and tertiary amines, such as alkyl amines (i.e., NH₂(alkyl)),dialkyl amines (i.e., HN(alkyl)₂), trialkyl amines (i.e., N(alkyl)₃),substituted alkyl amines (i.e., NH₂(substituted alkyl)), di(substitutedalkyl) amines (i.e., HN(substituted alkyl)₂), tri(substituted alkyl)amines (i.e., N(substituted alkyl)₃), alkenyl amines (i.e.,NH₂(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)₂), dialkenyl amines(i.e., N(alkenyl)₃), substituted alkenyl amines (i.e., NH₂(substitutedalkenyl)), di(substituted alkenyl) amines (i.e., HN(substitutedalkenyl)₂), tri(substituted alkenyl) amines (i.e., N(substitutedalkenyl)₃, mono-, di- or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl),HN(cycloalkyl)₂, N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e.,NH₂(aryl), HN(aryl)₂, N(aryl)₃) or mixed amines, etc. Specific examplesof suitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine and the like.

The term “hydrate” refers to the complex formed by the combining of acompound described herein and water.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the disclosure. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid andethanolamine.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

The compounds of the invention, or their pharmaceutically acceptablesalts include an asymmetric center and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)− or (S)− or, as(D)− or (L)− for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)− and (S)−, or (D)− and (L)−isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers,”which refers to two stereoisomers whose molecules are nonsuperimposablemirror images of one another.

“Diastereomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

“Prodrugs” means any compound which releases an active parent drugaccording to a structure described herein in vivo when such prodrug isadministered to a mammalian subject. Prodrugs of a compound describedherein are prepared by modifying functional groups present in thecompound described herein in such a way that the modifications may becleaved in vivo to release the parent compound. Prodrugs may be preparedby modifying functional groups present in the compounds in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent compounds. Prodrugs include compounds describedherein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in acompound described herein is bonded to any group that may be cleaved invivo to regenerate the free hydroxy, amino, or sulfhydryl group,respectively. Examples of prodrugs include, but are not limited toesters (e.g., acetate, formate and benzoate derivatives), amides,guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxyfunctional groups in compounds described herein and the like.Preparation, selection and use of prodrugs is discussed in T. Higuchiand V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of theA.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard,Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press, 1987,each of which are hereby incorporated by reference in their entirety.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” or “excipient” includes any andall solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutically active substances is wellknown in the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

2. Compounds

Provided herein are compounds that are useful as inhibitors of LRRK2.

In one embodiment, provided is a compound of formula I:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R¹ is optionally substituted cycloalkyl or, when R⁵ is —CR^(5a)R⁶R⁷where R^(5a) is optionally substituted triazol-2-yl, R¹ is optionallysubstituted cycloalkyl or C₁₋₆ alkyl optionally substituted with halo;

R² is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²);

R³ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R¹¹)(R¹²);

R⁴ is hydrogen or halo;

R⁵ is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²);

R⁶ and R⁷ are each independently H or optionally substituted C₁₋₆ alkyl;

each R¹⁰ is independently optionally substituted C₁₋₆ alkyl oroptionally substituted C₁₋₆ alkoxy; and

R¹¹ and R¹² are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R¹¹ and R¹² together forman optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula I represented byformula Ia:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R², R³ andR⁴ are as defined herein, and:

R¹ is optionally substituted cycloalkyl or C₁₋₆ alkyl optionallysubstituted with halo;

R⁶ and R⁷ are each independently hydrogen or C₁₋₆ alkyl optionallysubstituted with halo; and

R⁸ and R⁹ are each independently hydrogen, cyano, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, oroptionally substituted heteroaryl.

In certain embodiments, R⁶ and R⁷ are methyl.

In certain embodiments, R⁸ and R⁹ are hydrogen.

In certain embodiments, at least one of R⁸ and R⁹ is hydrogen.

In certain embodiments, R¹ is optionally substituted cyclopropyl oroptionally substituted cyclobutyl.

In certain embodiments, R¹ is cycloalkyl independently substituted withone or more halo, hydroxy, cyano, or heteroaryl.

In certain embodiments, R¹ is cyclopropyl, cyclobutyl,hydroxycylobut-3-yl, cyanocylobut-3-yl, triazol-2yl-cyclobut-3-yl,triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl.

In certain embodiments, R¹ is CD₃, ethyl, or prop-2-yl.

In certain embodiments, R² is halo, cyano, C₁₋₆ alkyl optionallysubstituted with halo.

In certain embodiments, R² is bromo.

In certain embodiments, R² is —CF₃.

In certain embodiments, R³ is optionally substituted cycloalkyl,optionally substituted C₁₋₆ alkoxy, or —N(R¹¹)(R¹²).

In certain embodiments, R³ is cyclopropyl, methoxy,1,1-difluoroeth-2-ylamino, cyclopropylamino, —NH(CH₃), or —NH(CH₂CH₃).

In certain embodiments, R⁴ is hydrogen.

In certain embodiments, R⁵ is cyano, optionally substituted C₁₋₆ alkyl,optionally substituted cycloalkyl, optionally substituted heterocyclyl,optionally substituted heteroaryl, optionally substituted C₁₋₆alkylsulfonyl, —C(O)R¹⁰, or —C(O)N(R¹¹)(R¹²).

In certain embodiments, R⁵ is cyano, —C(O)R¹⁰, —C(O)N(R¹¹)(R¹²), C₁₋₆alkylsulfonyl, acyl, heteroaryl optionally substituted with C₁₋₆ alkyl,cycloalkyl optionally substituted with one to three oxo or C₁₋₆ alkyl,heterocyclyl optionally substituted with one to three halo, C₁₋₆ alkyl,C₁₋₆ alkyl substituted with cyano, hydroxyl, alkylsulfonyl,heterocyclyl, hydroxy, alkoxy, or heteroaryl, or C₁₋₆ cycloalkylsubstituted with cyano, aminocarbonyl, or alkoxycarbonyl. In certainembodiments, R⁵ is cyano, —C(O)R¹⁰, —C(O)N(R¹¹)(R¹²), C₁₋₆alkylsulfonyl, acyl, heteroaryl optionally substituted with C₁₋₆ alkyl,heterocyclyl optionally substituted with C₁₋₆ alkyl, C₁₋₆ alkylsubstituted with cyano, hydroxyl, alkylsulfonyl, heterocyclyl, hydroxy,alkoxy, or heteroaryl, or C₁₋₆ cycloalkyl substituted with cyano,aminocarbonyl, or alkoxycarbonyl.

In certain embodiments, R⁵ is 2-(triazol-2-yl)propan-2-yl,2-pyrimidin-2-ylpropan-2-yl, N,N-dimethylamido, 2-methylpropan-2-yl,methylsulfonyl, cyano, 2-hydroxypropan-2-yl, methylcarbonyl,5-methylpyrrolidin-2-one-5-yl, 1-(triazol-2-yl)ethyl,2-methylsulfonylpropan-2-yl, 5-methyl-1,3-oxazol-4-yl)pyrazol-3-yl,3-methyloxetan-3-yl, 1-cyano-cycloprop-2-yl, pyrrolidin-2-one-5-yl,1,1-dioxo-1,2-thiazolidin-2-yl,7-methyl-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl,1-ethoxycarbonyl-cycloprop-2-yl, 1-aminocarbonyl-cycloprop-2-yl,7-methyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl,2-methoxypropan-2-yl, 2-cyanopropan-2-yl, 3-methyloxolan-2-one-3-yl,oxabicyclo[3.1.0]hexan-2-one-3-yl, 1-methyl-pyrrolidin-2-one-yl,cyclopropyl, 1-ethyl-4,4-difluoropiperid-3-yl, 4,4-difluoropiperid-3-yl,or 2-methyl-1-oxo-cyclopent-2-yl. In certain embodiments, R⁵ is2-(triazol-2-yl)propan-2-yl, 2-pyrimidin-2-ylpropan-2-yl,N,N-dimethylamido, 2-methylpropan-2-yl, methylsulfonyl, cyano,2-hydroxypropan-2-yl, methylcarbonyl, 5-methylpyrrolidin-2-one-5-yl,1-(triazol-2-yl)ethyl, 2-methylsulfonylpropan-2-yl,5-methyl-1,3-oxazol-4-yl)pyrazol-3-yl, 3-methyloxetan-3-yl,1-cyano-cycloprop-2-yl, pyrrolidin-2-one-5-yl,1,1-dioxo-1,2-thiazolidin-2-yl,7-methyl-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl,1-ethoxycarbonyl-cycloprop-2-yl, 1-aminocarbonyl-cycloprop-2-yl,7-methyl-5,6-dihydropyrrolo[1,2-b][1,2,4]triazol-7-yl,2-methoxypropan-2-yl, 2-cyanopropan-2-yl, 3-methyloxolan-2-one-3-yl,oxabicyclo[3.1.0]hexan-2-one-3-yl, or 1-methyl-pyrrolidin-2-one-yl.

In certain embodiments, R¹ is cycloalkyl independently substituted withone or more hydroxy, cyano, or heteroaryl; R² is halo or C₁₋₆fluoroalkyl; R³ is —N(R¹¹)(R¹²) or C₁₋₆ alkoxy; and R⁴ is hydrogen.

In certain embodiments, certain compounds provided herein aresurprisingly brain penetrant. In certain embodiments, the compoundsfurther have an MDR1-MDCK efflux ratio of less than or equal to aboutfive. In certain embodiments, these compounds are of formula Ia or Ib.

In one embodiment, provided is a compound of formula I represented byformula Ib:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R¹ is optionally substituted cycloalkyl or C₁₋₆ alkyl optionallysubstituted with halo;

R² is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²);

R¹⁰ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; and

each R¹¹ and R¹² are independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R¹¹ and R¹² together forman optionally substituted heterocyclyl group.

In certain embodiments, R¹ is optionally substituted cyclopropyl.

In certain embodiments, R¹ is cyclopropyl.

In certain embodiments, R¹ is methyl optionally substituted with halo.

In certain embodiments, R¹ is —CD₃.

In certain embodiments, R¹ is —CF₃.

In certain embodiments, R² is halo, cyano, or C₁₋₆ alkyl optionallysubstituted with halo.

In certain embodiments, R² is bromo.

In certain embodiments, R² is —CF₃.

In certain embodiments, R¹² is optionally substituted C₁₋₆ alkyl.

In certain embodiments, R¹² is ethyl.

In certain embodiments, R¹ is optionally substituted cyclopropyl ormethyl optionally substituted with halo; R² is halo, cyano, or C₁₋₆alkyl optionally substituted with halo; and R¹² is optionallysubstituted C₁₋₆ alkyl.

In one embodiment, provided is a compound of formula II:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R²⁰ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R²³;

R²¹ is optionally substituted cycloalkyl, heteroaryl, C₁₋₆ alkoxy,—S—C₁₋₆ alkyl, or —N(R²⁴)(R²⁵);

m is 0, 1, 2, 3, or 4;

each R²² is independently halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ aminoalkyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkylheteroarylalkyl, heteroarylcycloalkyl, alkylheteroarylcycloalkyl,amido, amidoalkyl, or —C(O)R²⁶, wherein each C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl, C₁₋₆ aminoalkyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylalkyl, cycloalkyl,cyanocycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl,alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,alkylheteroarylalkyl, heteroarylcycloalkyl, andalkylheteroarylcycloalkyl is optionally substituted; or

two R²² together with the atom to which they are attached form acycloalkyl or heterocyclyl, wherein each cycloalkyl and heterocyclyl isoptionally substituted;

R²³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R²⁷)₂, or heterocyclyl, wherein eachC₁₋₆ alkyl, C₁₋₆ alkoxy and heterocyclyl is optionally substituted;

R²⁴ and R²⁵ are each independently H or optionally substituted C₁₋₆alkyl; or

R²⁴ and R²⁵ together with the atom to which they are attached form anoptionally substituted heterocyclyl;

R²⁶ is C₁₋₆alkyl or heterocyclyl, wherein C₁₋₆ alkyl, C₁₋₆ haloalkyl,and heterocyclyl is independently optionally substituted with one ormore substituents selected from halo, cyano, hydroxy, C₁₋₆ alkoxy, andC₁₋₆ alkylsulfonyl;

each R²⁷ is independently H or optionally substituted C₁₋₆ alkyl; and

A is a heterocyclyl or heteroaryl ring fused to the pyrazole.

In one embodiment, ring A contains additional heteroatoms. In oneembodiment, ring A contains only the bridgehead nitrogen shared with thepyrazole ring.

In one embodiment, provided is a compound of formula IIA:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R²⁰, R²¹,R²² and m are as defined herein.

In one embodiment, provided is a compound of formula IIB:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R²⁰, R²¹,R²² and m are as defined herein.

In one embodiment, provided is a compound of formula IIA-a:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R²⁰, R²¹,R²² and m are as defined herein.

In one embodiment, provided is a compound of formula IIA-b:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R²⁰, R²¹,R²² and m are as defined herein.

In certain embodiments, R²⁰ is halo, cyano, C₁₋₆ alkyl, or C₁₋₆haloalkyl. In certain embodiments, R²¹ is C₁₋₆ haloalkyl. In certainembodiments, R²⁰ is C₁₋₆ haloalkyl.

In certain embodiments, R²² is optionally substituted cycloalkyl or—N(R²⁴)(R²⁵). In certain embodiments, R²¹ is optionally substitutedcycloalkyl, C₁₋₆ alkoxy or —N(R²⁴)(R²⁵).

In certain embodiments, R²² is independently halo, cyano, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆ cyanoalkyl,C₁₋₆ aminoalkyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylsulfonylalkyl,cycloalkyl, cyanocycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, alkylheterocyclylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, alkylheteroarylalkyl, heteroarylcycloalkyl,alkylheteroarylcycloalkyl, amido, amidoalkyl, or —C(O)R²⁶, wherein eachC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ alkoxyalkyl, C₁₋₆cyanoalkyl, C₁₋₆ aminoalkyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylsulfonylalkyl, cycloalkyl, cyanocycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, alkylheterocyclylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, alkylheteroarylalkyl,heteroarylcycloalkyl, and alkylheteroarylcycloalkyl is optionallysubstituted.

In certain embodiments, R²² is independently halo, cyano, C₁₋₆ alkyl, orheteroaryl.

In certain embodiments, two R²² together with the atom to which they areattached form a cycloalkyl or heterocyclyl, wherein each cycloalkyl andheterocyclyl is optionally substituted. In certain embodiments, two R²²together with the atom to which they are attached form a heterocyclyl.

In one embodiment, provided is a compound of formula III:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

n is 0 or 1;

R³⁰ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R³³;

R³¹ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R³⁵)(R³⁶);

R³² is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted C₁₋₆ alkylthio,optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R³⁴, or—C(O)N(R³⁵)(R³⁶);

R³³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R³⁵)(R³⁶), or heterocyclyl, whereineach C₁₋₆ alkyl, C₁₋₆ alkoxy, and heterocyclyl is optionallysubstituted;

R³⁴ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; and

R³⁵ and R³⁶ are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R³⁵ and R³⁶ together forman optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IIIA:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R³⁰ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R³³;

R³¹ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R³⁵)(R³⁶);

R³² is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted C₁₋₆ alkylthio,optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R³⁴, or—C(O)N(R₃₅)(R₃₆);

R³³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R³⁵)(R³⁶), or heterocyclyl, whereineach C₁₋₆ alkyl, C₁₋₆ alkoxy, and heterocyclyl is optionallysubstituted;

R³⁴ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; R³⁵ and R³⁶ are each independently hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted cycloalkyl, or R³⁵ andR³⁶ together form an optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IIIB:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R³⁰ is halo, cyano, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, cycloalkyl, cycloalkoxy, cycloalkylalkyl, cycloalkylalkoxy,or —C(O)R³³;

R³ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R³⁵)(R³⁶);

R³² is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted C₁₋₆ haloalkyl, optionally substitutedC₁₋₆ alkoxy, optionally substituted C₁₋₆ haloalkoxy, optionallysubstituted cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl, optionally substituted C₁₋₆ alkylthio,optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R³⁴, or—C(O)N(R³⁵)(R³⁶);

R³³ is C₁₋₆ alkyl, C₁₋₆ alkoxy, —N(R³⁵)(R³⁶), or heterocyclyl, whereineach C₁₋₆ alkyl, C₁₋₆ alkoxy and heterocyclyl is optionally substituted;

R³⁴ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; and

R³⁵ and R³⁶ are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R³⁵ and R³⁶ together forman optionally substituted heterocyclyl group.

In certain embodiments, R³ is halo, cyano, C₁₋₆ alkyl, or C₁₋₆haloalkyl. In certain embodiments, R³ is C₁₋₆ haloalkyl.

In certain embodiments, R³ is optionally substituted cycloalkyl, C₁₋₆alkoxy or —N(R³⁵)(R³⁶). In certain embodiments, R³ is optionallysubstituted cycloalkyl or —N(R³⁵)(R³⁶). In certain embodiments, R³ iscycloalkyl or —N(R³⁵)(R³⁶). In certain embodiments, R³ is —N(R³⁵)(R³⁶).

In certain embodiments, R³² is hydrogen, halo, cyano, C₁₋₆ alkyl, C₁₋₆alkenyl, C₁₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,cycloalkyl, heterocyclyl, heteroaryl, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, —C(O)R³⁴, or —C(O)N(R³⁵)(R³⁶). In certain embodiments,R³² is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ haloalkyl, optionally substituted C₁₋₆alkoxy, or optionally substituted C₁₋₆ haloalkoxy. In certainembodiments, R³² is hydrogen. In certain embodiments, R³² is halo. Incertain embodiments, R³² is methyl.

In one embodiment, provided is a compound of formula IVA:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

W is O, C(R⁴⁶)(R⁴⁷) or N(R⁴⁶);

R⁴⁰ is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R⁴⁸, or—C(O)N(R⁴⁹)(R⁵⁰);

R⁴¹ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R⁴⁹)(R⁵⁶);

R⁴² is optionally substituted cycloalkyl or C₁₋₆ alkyl optionallysubstituted with halo;

R⁴³ is hydrogen or halo;

R⁴⁴ is H or C₁₋₃ alkyl optionally substituted with halo;

each R⁴⁵ independently is halo, oxo, or optionally substituted C₁₋₃alkyl;

n is 1, 2, 3, or 4;

R⁴⁶ and R⁴⁷ are independently H, halo, optionally substituted C₁₋₃alkyl, optionally substituted cycloalkyl, or optionally substitutedheterocyclyl;

R⁴⁸ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; and

R⁴⁹ and R⁵ are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R⁴⁹ and R⁵ together form anoptionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IVA-a:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein W, R⁴³,R⁴⁴, R⁴⁵, and n are as defined herein, and:

R⁴⁰ is halo or C₁₋₆ haloalkyl;

R⁴¹ is —N(R⁴⁹)(R⁵⁰);

R⁴² is optionally substituted cyclopropyl;

R⁴⁹ is hydrogen; and

R⁵⁰ is optionally substituted C₁₋₆ alkyl.

In one embodiment, the compound is not3-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)pyrrolidin-2-one,3-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-3-methylpyrrolidin-2-one,3-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)pyrrolidin-2-one,or3-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-3-methylpyrrolidin-2-one,or a stereoisomer thereof.

In one embodiment, provided is a compound of formula IVA-b:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein W, R⁴³,R⁴⁴, R⁴⁵, and n are as defined herein, and:

R⁴¹ is halo or C₁₋₆ haloalkyl;

R⁴¹ is —N(R⁴⁹)(R⁵⁰);

R⁴² is optionally substituted cyclopropyl;

R⁴⁹ is hydrogen; and

R⁵⁰ is optionally substituted C₁₋₆ alkyl.

In one embodiment, provided is a compound of formula IVB:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R⁴⁰ is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R⁴⁸, or—C(O)N(R⁴⁹)(R⁵⁰);

R⁴ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R⁴⁹)(R⁵⁶);

R⁴² is optionally substituted cycloalkyl or C₁₋₆ alkyl optionallysubstituted with halo;

R⁴³ is hydrogen or halo;

each R⁴⁴ is independently H or C₁₋₃ alkyl optionally substituted withhalo;

each R⁴⁵ independently is halo, oxo, or optionally substituted C₁₋₃alkyl;

n is 1, 2, 3, or 4;

R⁴⁶ is H, halo, optionally substituted C₁₋₃ alkyl, optionallysubstituted cycloalkyl, or optionally substituted heterocyclyl;

R⁴⁸ is optionally substituted C₁₋₆ alkyl or optionally substituted C₁₋₆alkoxy; and

R⁴⁹ and R⁵⁰ are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R⁴⁹ and R⁵⁰ together forman optionally substituted heterocyclyl group.

In one embodiment, provided is a compound of formula IVB-a:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R⁴³, R⁴⁴,R⁴⁵, R⁴⁶, and n are as defined herein, and:

R⁴⁰ is halo or C₁₋₆ haloalkyl;

R⁴¹ is —N(R⁴⁹)(R⁵⁰);

R⁴² is optionally substituted cyclopropyl;

R⁴⁹ is hydrogen; and

R⁵⁰ is optionally substituted C₁₋₆ alkyl.

In one embodiment, the compound is not5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,5-(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,5-(3-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-2-one,5-(5-methyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)piperidin-2-one,N4-ethyl-N2-[5-methyl-1-((S)-1-oxetan-3-yl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,N4-ethyl-N2-[3-methyl-1-((S)-1-oxetan-3-yl)-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,N4-ethyl-N2-[5-methyl-1-((S)-1-methyl-piperidin-3yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,orN4-ethyl-N2-[3-methyl-1-((S)-1-methyl-piperidin-3-yl)-1H-pyrazol-4-yl]-5-trifluoromethyl-pyrimidine-2,4-diamine,or a stereoisomer thereof.

In one embodiment, the compound is not5-(4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,N-(5-chloro-1-(4,4-difluoro-1-(oxetan-3-yl)piperidin-3-yl)-1H-pyrazol-4-yl)-4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-amine,or5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-ethylpiperidin-2-one,5-(4-((4-cyclopropyl-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5-methyl-1H-pyrazol-1-yl)-1-methylpiperidin-2-one,or a stereoisomer thereof.

In one embodiment, provided is a compound of formula IVB-b:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein R⁴³, R⁴⁴,R⁴⁵, R⁴⁶, and n are as defined herein, and:

R⁴⁰ is halo or C₁₋₆ haloalkyl;

R⁴¹ is —N(R⁴⁹)(R⁵⁰);

R⁴² is optionally substituted cyclopropyl;

R⁴⁹ is hydrogen; and

R⁵⁰ is optionally substituted C₁₋₆ alkyl.

In one embodiment, provided is a compound of formula V:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein:

R⁶⁰ is halo, cyano, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkenyl, optionally substituted C₁₋₆ alkynyl,optionally substituted cycloalkyl, optionally substituted C₁₋₆ alkoxy,optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R⁶⁴, or—C(O)N(R⁶⁵)(R⁶⁶);

R⁶¹ is optionally substituted C₁₋₆ alkoxy, optionally substitutedcycloalkyl, optionally substituted cycloalkoxy, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, or—N(R⁶⁵)(R⁶⁶);

R⁶² is hydrogen or halo;

R⁶³ is hydrogen, halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₆ alkenyl, optionally substituted C₁₋₆alkynyl, optionally substituted cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, optionally substitutedC₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R⁶⁴, or—C(O)N(R⁶⁵)(R⁶⁶);

each R⁶⁴ is independently optionally substituted C₁₋₆ alkyl oroptionally substituted C₁₋₆ alkoxy; and

R⁶⁵ and R⁶⁶ are each independently hydrogen, optionally substituted C₁₋₆alkyl, optionally substituted cycloalkyl, or R⁶⁵ and R⁶⁶ together forman optionally substituted heterocyclyl group.

In one embodiment, the compound is notN2-(3-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,N2-(5-cyclopropyl-1-methyl-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine,1-(3-cyclopropyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,1-(3-cyclopropyl-4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropan-2-ol,2-(3-cyclopropyl-4-(4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-1H-pyrazol-1-yl)-2-methylpropanenitrile,or2-[4-(5-chloro-4-methoxy-pyrimidin-2-ylamino)-3-cyclopropyl-pyrazol-1-yl]-2-methyl-propionitrile,or a stereoisomer thereof.

In one embodiment, provided is a compound as shown in Table 1A or apharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof.

TABLE 1A No. Structure  1

 2

 3

 4

 5

 6

 7

 8

 9

 10

 11

 12

 13

 14

 15

 16

 17

 18

 19

 20

 21

 22

 23

  (First eluting isomer)  24

  (Second eluting isomer)  25

 26

 27

 28

  (First eluting isomer)  29

  (Second eluting isomer)  30

  (First eluting isomer)  31

  (Second eluting isomer)  32

 33

 35

 35A

 35B

 36

 37

 38

 39

 39A

 40

 41

 42

 43

 44

 45

 46

 47

 48

 49

 50

 51

 52A

  (First eluting isomer)  52B

  (Second eluting isomer)  53

 54A

  (First eluting isomer)  54B

  (Second eluting isomer)  55

 56

 58

 59

 60

 61

 62

 63

 64A

  (First eluting isomer)  64B

  (Second eluting isomer)  65

 66

 67

 72

 73

 74

 76

 80

 84

 85

 87

 89

 90

  (Second eluting isomer)  91

  (Second eluting isomer)  92

  (Second eluting isomer)  93

 94

 95

 96

 97

 98

 99

  (Second eluting isomer) 100

  (First eluting isomer) 101

102

  (First eluting isomer) 103

  (Second eluting isomer) 104

  (First eluting isomer) 105

106

107

108

109

110

111

112

113

  (Second eluting isomer) 114

  (First eluting isomer) 115

  (Second eluting isomer) 116

  (First eluting isomer) 117

  (Second eluting isomer) 118

119

  (Second eluting isomer) 120

  (First eluting isomer) 121

122

  (First eluting isomer) 123

  (First eluting isomer) 124

  (First eluting isomer) 125

  (Second eluting isomer) 194

195

196

197

198

199

200

  (first eluting isomer) 201

  (second eluting isomer) 202

  (first eluting isomer) 203

  (second eluting isomer) 204

  (first eluting isomer) 205

  (second eluting isomer) 206

  (second eluting isomer) 207

  (first eluting isomer) 208

  (first eluting isomer) 209

  (second eluting isomer) 210

  (first eluting isomer) 211

  (second eluting isomer) 212

  (first eluting isomer) 213

  (second eluting isomer) 214

  (first eluting isomer) 215

  (second eluting isomer) 216

  (First eluting isomer) 217

  (second eluting isomer) 218

In some embodiments, the compound is in Table 1B or is apharmaceutically acceptable salt, prodrug, tautomer, stereoisomer, or amixture of stereoisomers thereof:

TABLE 1B No. Structure 34

57

68

69

70

71

75

77

78

79

81

82

83

86

88

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

In one embodiment, a compound may be selected from those compounds inTable 1A. Also included within the disclosure are pharmaceuticallyacceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomersthereof. In certain embodiments, provided are compounds of Table 1A foruse in the methods described herein.

In one embodiment, a compound may be selected from those compounds inTable 1B. Also included within the disclosure are pharmaceuticallyacceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomersthereof. In certain embodiments, provided are compounds of Table 1B foruse in the methods described herein.

Specific stereoisomers contemplated include the following in Table 2Aand Table 2B.

TABLE 2A Structure

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof.

TABLE 2B Structure

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof.

In one embodiment, a compound may be selected from those compounds inTable 2A. Also included within the disclosure are pharmaceuticallyacceptable salts, prodrugs, stereoisomers, or a mixture of stereoisomersthereof. In one embodiment, a compound may be selected from thosecompounds in Table 2B. Also included within the disclosure arepharmaceutically acceptable salts, deuterated analogs, prodrugs,stereoisomers, or a mixture of stereoisomers thereof. In certainembodiments, provided are compounds of Table 2A for use in the methodsdescribed herein. In certain embodiments, provided are compounds ofTable 2B for use in the methods described herein.

3. Treatment Methods and Uses

“Treatment” or “treating” is an approach for obtaining beneficial ordesired results including clinical results. Beneficial or desiredclinical results may include one or more of the following: a) inhibitingthe disease or condition (e.g., decreasing one or more symptomsresulting from the disease or condition, and/or diminishing the extentof the disease or condition); b) slowing or arresting the development ofone or more clinical symptoms associated with the disease or condition(e.g., stabilizing the disease or condition, preventing or delaying theworsening or progression of the disease or condition, and/or preventingor delaying the spread (e.g., metastasis) of the disease or condition);and/or c) relieving the disease, that is, causing the regression ofclinical symptoms (e.g., ameliorating the disease state, providingpartial or total remission of the disease or condition, enhancing effectof another medication, delaying the progression of the disease,increasing the quality of life and/or prolonging survival.

“Prevention” or “preventing” means any treatment of a disease orcondition that causes the clinical symptoms of the disease or conditionnot to develop. Compounds may, in some embodiments, be administered to asubject (including a human) who is at risk or has a family history ofthe disease or condition.

“Subject” refers to an animal, such as a mammal (including a human),that has been or will be the object of treatment, observation orexperiment. The methods described herein may be useful in human therapyand/or veterinary applications. In some embodiments, the subject is amammal. In one embodiment, the subject is a human.

The term “therapeutically effective amount” or “effective amount” of acompound described herein or a pharmaceutically acceptable salt,deuterated analog, tautomer, stereoisomer, mixture of stereoisomers,prodrug, or deuterated analog thereof means an amount sufficient toeffect treatment when administered to a subject, to provide atherapeutic benefit such as amelioration of symptoms or slowing ofdisease progression. For example, a therapeutically effective amount maybe an amount sufficient to decrease a symptom of a disease or conditionof as described herein. The therapeutically effective amount may varydepending on the subject, and disease or condition being treated, theweight and age of the subject, the severity of the disease or condition,and the manner of administering, which can readily be determined by oneof ordinary skill in the art.

The methods described herein may be applied to cell populations in vivoor ex vivo. “In vivo” means within a living individual, as within ananimal or human. In this context, the methods described herein may beused therapeutically in an individual. “Ex vivo” means outside of aliving individual. Examples of ex vivo cell populations include in vitrocell cultures and biological samples including fluid or tissue samplesobtained from individuals. Such samples may be obtained by methods wellknown in the art. Exemplary biological fluid samples include blood,cerebrospinal fluid, urine, and saliva. In this context, the compoundsand compositions described herein may be used for a variety of purposes,including therapeutic and experimental purposes. For example, thecompounds and compositions described herein may be used ex vivo todetermine the optimal schedule and/or dosing of administration of acompound of the present disclosure for a given indication, cell type,individual, and other parameters. Information gleaned from such use maybe used for experimental purposes or in the clinic to set protocols forin vivo treatment. Other ex vivo uses for which the compounds andcompositions described herein may be suited are described below or willbecome apparent to those skilled in the art. The selected compounds maybe further characterized to examine the safety or tolerance dosage inhuman or non-human subjects. Such properties may be examined usingcommonly known methods to those skilled in the art.

LRRK2 has been associated with the transition from mild cognitiveimpairment to Alzheimer's disease; L-Dopa induced dyskinesia (Hurley etal., Eur. J, Neurosci., Vol. 26, 2007, 171-177); CNS disordersassociated with neuroprogenitor cell proliferation and migration, andregulation of LRRK2 may have utility in improving neurological outcomesfollowing ischemic injury, and stimulating restoration of CNS functionfollowing neuronal injury such as ischemic stroke, traumatic braininjury, or spinal cord injury (Milosevic et al., Neurodegen., Vol. 4,2009, 25; See Zhang et al., J. Neurosci. Res. Vol. 88, 2010, 3275-3281);Parkinson's disease, Alzheimer's disease, multiple sclerosis, andHIV-induced dementia (See Milosevic et al., Mol. Neurodegen., Vol. 4,2009, 25); kidney, breast, prostate (e.g. solid tumor), blood and lungcancer, and acute myeologenouse leukemia (AML); lymphomas and leukemias(See Ray et al., J. Immunolo., Vol. 230, 2011, 109); multiple myeoloma(Chapman et al., Nature, Vol. 471, 2011, 467-472); papillary renal andthyroid carcinomas; multiple myeloma (Chapman et al., Nature, Vol. 471,2011, 467-472); diseases of the immune system, including rheumatoidarthritis, systemic lupus erythematosus autoimmune hemolytic anemia,pure red cell aplasia, idiopathic thrombocytopenic pupura (ITP), Evanssyndrome, vasculitis, bullous skin disorders, type 1 diabetes mellitus,Sjogren's syndrome, Delvic's disease, and inflammatory myopathies(Nakamura et al., DNA Res. Vol. 13(4), 2006, 169-183; See Engel et al.,Pharmacol. Rev. Vol. 63, 2011, 127-156; Homam et al., J. Clin.Neuromuscular Disease, Vol. 12, 2010, 91-102); ankylosing spondylitisand leprosy infection (DAnoy et al., PLoS Genetics, Vol. 6(12), 2010,e1001195, 1-5; see Zhang et al., N. Eng. J. Med. Vol. 361, 2009,2609-2618); alpha-synucleinopathies, taupathies (See Li et al., 2010Neurodegen. Dis. Vol. 7, 2010, 265-271); Gaucher disease (See Westbroeket al., Trends. Mol. Med. Vol. 17, 2011, 485-493); tauopathy diseasescharacterized by hyperphosphorylation of Tau such as argyrophilic graindisease, Pick's disease, corticobasal degeneration, progressivesupranuclear palsy, and inherited frontotemporal dementia andparkinsonism linked to chromosome 17 (See Goedert, M and Jakes, R,Biochemica et Biophysica Acta, Vol. 1739, 2005, 240-250); diseasescharacterized by diminished dopamine levels such as withdrawalsymptoms/relapse associated with drug addiction (See Rothman et al., og.Brain Res., Vol. 172, 2008, 385); microglial proinflammatory responses(See Moehle et al., J. Neuroscience Vol. 32, 2012, 1602-1611); Crohn'sdisease pathogenesis (see Barrett et al., Nature Genetics, Vol. 40,2008, 955-962); and amyotrophic lateral sclerosis (ALS).

It is suggested that increased LRRK2 activity may be characteristic ofALS. Significantly elevated levels of LRRK2 mRNA have been observed infibroblasts of Niemann-Pick Type C (NPC) disease patients, indicatingabnormal LRRK2 function may play a role in lysosomal disorders.

In another aspect, the present disclosure relates to a method oftreating a disease or condition mediated, at least in part, by LRRK2. Inparticular, the disclosure provides methods for preventing or treating adisorder associated with LRRK2 in a mammal, comprising the step ofadministering to said mammal a therapeutically effective amount of acompound of Table 1A or Table 1B or therapeutic preparation of thepresent disclosure. In some embodiments, the disease or conditionmediated, at least in part, by LRRK2 is a neurodegenerative disease, forexample, a central nervous system (CNS) disorder, such as Parkinson'sdisease (PD), Alzheimer's disease (AD), dementia (including Lewy bodydementia and cascular dementia), amyotrophic lateral sclerosis (ALS),age related memory dysfunction, mild cognitive impairment (e.g.,including the transition from mild cognitive impairment to Alzheimer'sdisease), argyrophilic grain disease, lysosomal disorders (for example,Niemann-PickType C disease, Gaucher disease) corticobasal degeneration,progressive supranuclear palsy, inherited frontotemporal dementia andparkinsonism linked to chromosome 17 (FTDP-17), withdrawalsymptoms/relapse associated with drug addiction, L-Dopa induceddyskinesia, Huntington's disease (HD), and HIV-associated dementia(HAD). In other embodiments, the disorder is an ischemic disease oforgans including but not limited to brain, heart, kidney, and liver.

In some other embodiments, the disease or condition mediated, at leastin part, by LRRK2 is cancer. In certain specific embodiments, the canceris thyroid, renal (including papillary renal), breast, lung, blood, andprostate cancers (e.g. solid tumor), leukemias (including acutemyelogenous leukemia (AML)), or lymphomas. In some embodiments, thecancer is kidney cancer, breast cancer, prostate cancer, blood cancer,papillary cancer, lung cancer, acute myelogenous leukemia, or multiplemyeloma.

In other embodiments, the presently disclosed compounds are used inmethods for treatment of inflammatory disorders. In some embodiments,the disorder is an inflammatory disease of the intestines, such asCrohn's disease or ulcerative colitis (both generally known together asinflammatory bowel disease). In other embodiments, the inflammatorydisease is leprosy, amyotrophic lateral sclerosis, rheumatoid arthritis,or ankylosing spondylitis. In some embodiments, the inflammatory diseaseis leprosy, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, amyotrophic lateral sclerosis, rheumatoid arthritis, orankylosing spondylitis.

In other embodiments, the presently disclosed compounds are used inmethods for treatment of multiple sclerosis, systemic lupuserythematosus, autoimmune hemolytic anemia, pure red cell aplasia,idiopathic thrombocytopenic purpura (ITP), Evans syndrome, vasculitis,bullous skin disorders, type 1 diabetes mellitus, Sjogren's syndrome,Devic's disease, and inflammatory myopathies.

Other embodiments include methods for enhancing cognitive memory of asubject, the method comprising administering an effective amount of acomposition comprising the compound of Table 1A, Table 1B, Table 2A orTable 2B to a subject in need thereof.

Other embodiments include use of the presently disclosed compounds intherapy. Some embodiments include their use in the treatment of aneurodegenerative disease, cancer, or an inflammatory disease.

In other embodiments, provided are the presently disclosed compounds foruse in the treatment of Alzheimer's disease, L-Dopa induced dyskinesia,Parkinson's disease, dementia, ALS, kidney cancer, breast cancer,prostate cancer, blood cancer, papillary cancer, lung cancer, acutemyelogenous leukemia, multiple myeloma, leprosy, Crohn's disease,inflammatory bowel disease, ulcerative colitis, amyotrophic lateralsclerosis, rheumatoid arthritis, or ankylosing spondylitis.

In other embodiments, provided is the use of the presently disclosedcompounds for the manufacture of a medicament for treating aneurodegenerative disease, cancer, or an inflammatory disease.

In other embodiments, provided is the use of the presently disclosedcompounds for the manufacture of a medicament for treating Alzheimer'sdisease, L-Dopa induced dyskinesia, Parkinson's disease, dementia,amyotrophic lateral sclerosis, kidney cancer, breast cancer, prostatecancer, blood cancer, papillary cancer, lung cancer, acute myelogenousleukemia, multiple myeloma, leprosy, Crohn's disease, inflammatory boweldisease, ulcerative colitis, amyotrophic lateral sclerosis, rheumatoidarthritis, or ankylosing spondylitis.

The term “trauma” as used herein refers to any physical damage to thebody caused by violence, accident, fracture etc. The term “ischemia”refers to a cardiovascular disorder characterized by a low oxygen stateusually due to the obstruction of the arterial blood supply orinadequate blood flow leading to hypoxia in the tissue. The term“stroke” refers to cardiovascular disorders caused by a blood clot orbleeding in the brain, most commonly caused by an interruption in theflow of blood in the brain as from clot blocking a blood vessel, and incertain embodiments of the disclosure the term stroke refers to ischemicstroke or hemorrhagic stroke. The term “myocardial infarction” refers toa cardiovascular disorder characterized by localized necrosis resultingfrom obstruction of the blood supply.

In certain embodiments, the present disclosure relates to compounds forinhibiting cell death, wherein the compounds are shown in Table 1A,Table 1B, Table 2A or Table 2B. In certain embodiments, the compounds ofthe present disclosure are inhibitors of cell death. In any event, thecompounds of the present disclosure preferably exert their effect oninhibiting cell death at a concentration less than about 50 micromolar,more preferably at a concentration less than about 10 micromolar, andmost preferably at a concentration less than 1 micromolar.

4. Kits

Provided herein are also kits that include a compound of the disclosure,or a pharmaceutically acceptable salt, deuterated analog, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof, and suitable packaging. In one embodiment, a kit furtherincludes instructions for use. In one aspect, a kit includes a compoundof the disclosure, or a pharmaceutically acceptable salt, deuteratedanalog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, ordeuterated analog thereof, and a label and/or instructions for use ofthe compounds in the treatment of the indications, including thediseases or conditions, described herein.

Provided herein are also articles of manufacture that include a compounddescribed herein or a pharmaceutically acceptable salt, deuteratedanalog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, ordeuterated analog thereof in a suitable container. The container may bea vial, jar, ampoule, preloaded syringe, and intravenous bag.

5. Pharmaceutical Compositions and Modes of Administration

Compounds provided herein are usually administered in the form ofpharmaceutical compositions. Thus, provided herein are alsopharmaceutical compositions that contain one or more of the compoundsdescribed herein or a pharmaceutically acceptable salt, deuteratedanalog, tautomer, stereoisomer, mixture of stereoisomers, prodrug, ordeuterated analog thereof and one or more pharmaceutically acceptablevehicles selected from carriers, adjuvants and excipients. Suitablepharmaceutically acceptable vehicles may include, for example, inertsolid diluents and fillers, diluents, including sterile aqueous solutionand various organic solvents, permeation enhancers, solubilizers andadjuvants. Such compositions are prepared in a manner well known in thepharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, MacePublishing Co., Philadelphia, Pa. 17th Ed. (1985); and ModernPharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker & C. T. Rhodes,Eds.).

The pharmaceutical compositions may be administered in either single ormultiple doses. The pharmaceutical composition may be administered byvarious methods including, for example, rectal, buccal, intranasal andtransdermal routes. In certain embodiments, the pharmaceuticalcomposition may be administered by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, or as an inhalant.

One mode for administration is parenteral, for example, by injection.The forms in which the pharmaceutical compositions described herein maybe incorporated for administration by injection include, for example,aqueous or oil suspensions, or emulsions, with sesame oil, corn oil,cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose,or a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of thecompounds described herein. Administration may be via, for example,capsule or enteric coated tablets. In making the pharmaceuticalcompositions that include at least one compound described herein or apharmaceutically acceptable salt, deuterated analog, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof, the active ingredient is usually diluted by an excipient and/orenclosed within such a carrier that can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be in the form of a solid, semi-solid, or liquidmaterial, which acts as a vehicle, carrier or medium for the activeingredient. Thus, the compositions can be in the form of tablets, pills,powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium),ointments containing, for example, up to 10% by weight of the activecompound, soft and hard gelatin capsules, sterile injectable solutions,and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions that include at least one compound described herein ora pharmaceutically acceptable salt, deuterated analog, tautomer,stereoisomer, mixture of stereoisomers, prodrug, or deuterated analogthereof can be formulated so as to provide quick, sustained or delayedrelease of the active ingredient after administration to the subject byemploying procedures known in the art. Controlled release drug deliverysystems for oral administration include osmotic pump systems anddissolutional systems containing polymer-coated reservoirs ordrug-polymer matrix formulations. Transdermal patches may be used toprovide continuous or discontinuous infusion of the compounds describedherein in controlled amounts. Transdermal patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound described herein or a pharmaceutically acceptable salt,deuterated analog, tautomer, stereoisomer, mixture of stereoisomers,prodrug, or deuterated analog thereof. When referring to thesepreformulation compositions as homogeneous, the active ingredient may bedispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

The tablets or pills of the compounds described herein may be coated orotherwise compounded to provide a dosage form affording the advantage ofprolonged action, or to protect from the acid conditions of the stomach.For example, the tablet or pill can include an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation may include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedherein. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect. In otherembodiments, compositions in pharmaceutically acceptable solvents may benebulized by use of inert gases. Nebulized solutions may be inhaleddirectly from the nebulizing device or the nebulizing device may beattached to a facemask tent, or intermittent positive pressure breathingmachine. Solution, suspension, or powder compositions may beadministered, preferably orally or nasally, from devices that deliverthe formulation in an appropriate manner.

6. Dosing

The specific dose level of a compound of the present application for anyparticular subject will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the subject undergoing therapy. Forexample, a dosage may be expressed as a number of milligrams of acompound described herein per kilogram of the subject's body weight(mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate.In some embodiments, a dosage of from about 0.1 and 100 mg/kg may beappropriate. In other embodiments a dosage of between 0.5 and 60 mg/kgmay be appropriate. In some embodiments, a dosage of from about 0.0001to about 100 mg per kg of body weight per day, from about 0.001 to about50 mg of compound per kg of body weight, or from about 0.01 to about 10mg of compound per kg of body weight may be appropriate. Normalizingaccording to the subject's body weight is particularly useful whenadjusting dosages between subjects of widely disparate size, such asoccurs when using the drug in both children and adult humans or whenconverting an effective dosage in a non-human subject such as dog to adosage suitable for a human subject.

The daily dosage may also be described as a total amount of a compounddescribed herein administered per dose or per day. Daily dosage of acompound of Table 1A, Table 1B, Table 2A or Table 2B may be betweenabout 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, betweenabout 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150mg/day.

When administered orally, the total daily dosage for a human subject maybe between 1 mg and 1,000 mg, between about 1,000-2,000 mg/day, betweenabout 10-500 mg/day, between about 50-300 mg/day, between about 75-200mg/day, or between about 100-150 mg/day.

The compounds of the present application or the compositions thereof maybe administered once, twice, three, four, or more times daily, using anysuitable mode described above.

In a particular embodiment, the method comprises administering to thesubject an initial daily dose of about 1 to 800 mg of a compounddescribed herein and increasing the dose by increments until clinicalefficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg canbe used to increase the dose. The dosage can be increased daily, everyother day, twice per week, or once per week.

7. Combination Therapy

In another aspect of the disclosure the compounds can be administered incombination with other agents, including (but not limited to) compoundsthat are apoptosis inhibitors; PARP poly(ADP-ribose) polymeraseinhibitors; Src inhibitors; agents for the treatment of cardiovasculardisorders; hypertension, hypercholesterolemia and type II diabetes;anti-inflammatory agents, anti-thrombotic agents; fibrinolytic agents;anti-platelet agents, lipid reducing agents, direct thrombin inhibitors;glycoprotein IIb/IIIa receptor inhibitors; calcium channel blockers;beta-adrenergic receptor blocking agents; cyclooxygenase (e.g., COX-1and COX-2) inhibitors; angiotensin system inhibitor (e.g.,angiotensin-converting enzyme (ACE) inhibitors); renin inhibitors;and/or agents that bind to cellular adhesion molecules and inhibit theability of white blood cells to attach to such molecules (e.g.,polypeptides, polyclonal and monoclonal antibodies).

In other embodiments, the compounds of the present disclosure can beadministered in combination with an additional agent having activity fortreatment of a neurodegenerative disease. For example, in someembodiments the compounds are administered in combination with one ormore additional therapeutic agents useful for treatment of Parkinson'sdisease. In some embodiments, the additional therapeutic agent is L-dopa(e.g., Sinemet®), a dopaminergic agonist (e.g. Ropinerol orPramipexole), a catechol-O-methyltransferase (COMT) inhibitor (e.g.Entacapone), a L-monoamine oxidase (MAO) inhibitor (e.g., selegiline orrasagiline) or an agent which increases dopamine release (e.g.,Zonisamide).

The present disclosure also provides combinations of two or morecompounds that inhibit cellular necrosis (e.g., a compound as disclosedherein and an additional agent for inhibiting necrosis). The presentdisclosure also provides combinations of one or more compounds thatinhibit cellular necrosis combined with one or more additional agents orcompounds (e.g., other therapeutic compounds for treating a disease,condition, or infection).

8. Synthesis of the Compounds

The compounds may be prepared using the methods disclosed herein androutine modifications thereof, which will be apparent given thedisclosure herein and methods well known in the art. Conventional andwell-known synthetic methods may be used in addition to the teachingsherein. The synthesis of typical compounds described herein may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g., from Sigma Aldrich orother chemical suppliers.

The compounds of the disclosure may be prepared using methods disclosedherein and routine modifications thereof which will be apparent giventhe disclosure herein and methods well known in the art. Conventionaland well-known synthetic methods may be used in addition to theteachings herein. The synthesis of the compounds described herein may beaccomplished as described in the following examples. If available,reagents may be purchased commercially, e.g. from Sigma Aldrich or otherchemical suppliers.

The compounds of this disclosure can be prepared from readily availablestarting materials using, for example, the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006).Greene's protective groups in organic synthesis. Hoboken, N.J.,Wiley-Interscience, and references cited therein.

Furthermore, the compounds of this disclosure may contain one or morechiral centers. Accordingly, if desired, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthis disclosure, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) may be prepared using, for example, optically activestarting materials or stereoselective reagents well-known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents, and the like.

The starting materials for the following reactions are generally knowncompounds or can be prepared by known procedures or obviousmodifications thereof. For example, many of the starting materials areavailable from commercial suppliers such as Aldrich Chemical Co.(Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemce orSigma (St. Louis, Mo., USA). Others may be prepared by procedures orobvious modifications thereof, described in standard reference textssuch as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15(John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds,Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989)organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March'sAdvanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989).

The terms “solvent,” “inert organic solvent” or “inert solvent” refer toa solvent inert under the conditions of the reaction being described inconjunction therewith (including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”),chloroform, methylene chloride (or dichloromethane), diethyl ether,methanol, pyridine and the like). Unless specified to the contrary, thesolvents used in the reactions of the present disclosure are inertorganic solvents, and the reactions are carried out under an inert gas,preferably nitrogen.

The term “q.s.” means adding a quantity sufficient to achieve a statedfunction, e.g., to bring a solution to the desired volume (i.e., 100%).

It will also be appreciated that in each of the above schemes, theaddition of any substituent may result in the production of a number ofisomeric products (including, but not limited to, enantiomers or one ormore diastereomers) any or all of which may be isolated and purifiedusing conventional techniques. When enantiomerically pure or enrichedcompounds are desired, chiral chromatography and/or enantiomericallypure or enriched starting materials may be employed as conventionallyused in the art or as described in the Examples.

General Synthesis

The following General Reaction Scheme I illustrates a general method ofmaking the compounds disclosed herein.

Referring to General Reaction Scheme I, compounds of formula (X) areprepared by coupling of a substituted pyrimidine of formula (Y) with anamine of formula (Z), wherein R², R³, ring B and m are defined as in anyof the formulas provided herein or by the specific compounds exemplifiedin Table 1A, Table 1B, Table 2A or Table 2B, and X is a leaving group.In certain embodiments, X is halo. Appropriate compounds of formula (Y)or (Z) can be prepared according to the more specific methods describedin the Examples which follow or by methods known to one of skill in theart. Coupling of compounds of formula (Y) and (Z) in presence of anacid, provides a compound of formula (X). In some embodiments, the acidis toluene sulfonic acid or trifluroacetic acid. In some embodiments,coupling of compounds of formula (Y) and (Z) in the presence of a baseprovides a compound of formula (X). In some embodiments, the base istriethylamine.

In one embodiment, provided is a method of preparing a compound offormula (X) comprising coupling a compound of formula (Y) with acompound of formula (Z) under conditions to provide the compound offormula (X), wherein R¹, R², R³, ring B and m are defined as in any ofthe formulas provided herein or by the specific compounds exemplified inTable 1A, Table 1B, Table 2A or Table 2B, and X is a leaving group. Incertain embodiments, X is halo.

When not commercially available, amines of formula (Z) can be preparedfrom commercially available starting materials. For example, in certainembodiments, amines of formula (Z) can be prepared from reducing thecorresponding nitro substituted compound. The amines of formula (Z) aretypically functionalized prior to the coupling with the substitutedpyrimidine of formula (Y). Where a certain stereoisomer is desired(e.g., a cis- or trans-stereoisomer of formula III, IIIA, or IIIB), asingle stereoisomer of the corresponding amine may be prepared prior tocoupling with the substituted pyrimidine of formula (Y). Each of thecis- and trans-stereoisomers can be prepared by selectively invertingthe stereochemistry prior to the installation of the cyano moiety on thecyclobutyl ring. In certain embodiments, amines of formula (Z) areprepared via 1,3-dipolar cycloaddition reactions using appropriatelyfunctionalized starting materials. Further functionalization orfunctional group interconversion may be performed before or after thecycloaddition reaction.

In certain embodiments, compounds of formula Ia can be preparedaccording to Scheme II.

Referring to General Reaction Scheme II, compounds of formula (2-3) canbe prepared by coupling appropriately substituted triazole (2-1) withappropriately substituted ester (2-2). Conversion of the ester ofcompound (2-3) to the α-cyanoketone compound (2-4) can be accomplishedunder substitution reaction conditions using a strong base (e.g.,butyllithium) and acetonitrile. Contacting compound (2-4) with anappropriately substituted hydrazine (2-5) or salt thereof, provides anamine of formula (2-6). Coupling of the amine of formula (2-6) with theappropriately substituted pyrimidine of formula (Y) can be accomplishedaccording to Scheme I, thus providing the compounds of formula Ia.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

General Experimental Methods:

All non-aqueous reactions were carried out in oven-dried or flame-driedglassware under nitrogen atmosphere. All chemicals were purchased fromcommercial vendors and used as is, unless otherwise specified. Reactionswere magnetically stirred and monitored by thin layer chromatography(TLC) with 250 μm pre-coated silica gel plates, visualized either withUV, or in an iodine chamber. Flash column chromatography was performedusing silica gel (100-200 mesh). Chemical shifts are reported relativeto chloroform (δ7.26), methanol (δ3.31), or DMSO (δ2.50) for ¹H NMR.HPLC analysis was performed on Shimadzu 20AB HPLC system with aphotodiode array detector and Luna-C18(2) 2.0×50 mm, 5 um column at aflow rate of 1.2 mL/min with a gradient solvent Mobile phase A (MPA,H₂O+0.037% (v/v) TFA): Mobile phase B (MPB, ACN+0.018% (v/v) TFA) (0.01min, 10% MPB; 4 min, 80% MPB; 4.9 min, 80% MPB; 4.92 min, 10% MPB; 5.5min, 10% MPB). LCMS was detected under 220 and 254 nm or usedevaporative light scattering (ELSD) detection as well as positiveelectrospray ionization (MS). Semi-preparative HPLC was performed byeither acidic or neutral condition. Acidic: Luna C18 100×30 mm, 5 μm;MPA: HCl/H₂O=0.04%, or formic acid/H₂O=0.2% (v/v); MPB: ACN. Neutral:Waters Xbridge 150×25, 5 μm; MPA: 10 mM NH₄HCO₃ in H₂O; MPB: ACN.Gradient for both conditions: 10% of MPB to 80% of MPB within 12 min ata flow rate of 20 mL/min, then 100% MPB over 2 min, 10% MPB over 2 min,UV detector. SFC analysis was performed on Thar analytical SFC systemwith a UV/Vis detector and series of chiral columns including AD-3,AS-H, OJ-3, OD-3, AY-3 and IC-3, 4.6×100 mm, 3 μm column at a flow rateof 4 mL/min with a gradient solvent Mobile phase A (MPA, CO₂): Mobilephase B (MPB, MeOH+0.05% (v/v) IPAm) (0.01 min, 10% MPB; 3 min, 40% MPB;3.5 min, 40% MPB; 3.56-5 min, 10% MPB). SFC preparative was performed onThar 80 preparative SFC system with a UV/Vis detector and series ofchiral preparative columns including AD-H, AS-H, OJ-H, OD-H, AY-H andIC-H, 30×250 mm, 5 μm column at a flow rate of 65 mL/min with a gradientsolvent Mobile phase A (MPA, CO₂): Mobile phase B (MPB, MeOH+0.1% (v/v)NH₃H₂O) (0.01 min, 10% MPB; 5 min, 40% MPB; 6 min, 40% MPB; 6.1-10 min,10% MPB).

Compounds were named by using either ChemBioDraw Ultra 13.0 or chemaxon.

Compound Preparation

Where the preparation of starting materials is not described, these arecommercially available, known in the literature or readily obtainable bythose skilled in the art using standard procedures. Where it is statedthat compounds were prepared analogously to earlier examples orintermediates, it will be appreciated by the skilled person that thereaction time, number of equivalents of reagents and temperature can bemodified for each specific reaction and that it may be necessary ordesirable to employ different work-up or purification techniques. Wherereactions are carried out using microwave irradiation, the microwaveused is a Biotage Initiator. The actual power supplied varies during thecourse of the reaction in order to maintain a constant temperature.

Example 1 Synthesis ofN4-ethyl-N2-[1-(3-isocyanocyclobutyl)-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(26) 3-(benzyloxy)cyclobutanol

To a stirring solution of 3-benzyloxycyclobutanone (125 g, 709.38 mmol)in MeOH (1.5 L) was added NaBH₄ (26.84 g, 709.38 mmol) portionwise at−20° C. under N₂ over a period of 4 h. After addition, the mixture wasallowed to warm to 25° C. and stirred for 30 min. The mixture was addedwith water (50 mL) and stirred for 30 min. The mixture was concentratedunder reduced pressure to give a residue. (Two batches of the same scalewere combined to workup.) The residue was purified by silica gel columnchromatography (PE:EtOAc=6:1) to afford(1S,3S)-3-(benzyloxy)cyclobutanol as a colorless oil.

1-(3-(benzyloxy)cyclobutyl)-4-nitro-1H-pyrazole

To a mixture of (1S,3S)-3-(benzyloxy)cyclobutanol (250 g, 1.40 mol) and4-nitro-1H-pyrazole (158.3 g, 1.40 mol) in THF (5 L) was added PPh₃(477.37 g, 1.82 mol) and DIAD (368.02 g, 1.82 mol, 353.87 mL) dropwiseat 0° C. under N₂. After addition, the mixture was stirred at 25° C. for16 h. The mixture was concentrated in reduced pressure to give aresidue. The residue was triturated with PE:EtOAc=2:1 (2 L) andfiltered. The filter cake was washed with PE:EtOAc=2:1 (2×1 L) and thecombined filtrate were concentrated to afford a crude product. The crudeproduct was purified by silica gel column chromatography (PE:EtOAc=6:1)to afford 1-((1R,3R)-3-(benzyloxy)cyclobutyl)-4-nitro-1H-pyrazole as awhite solid. LCMS: RT 0.851 min, m/z=274.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃) δ 8.15 (s, 1H), 8.12 (s, 1H), 7.29-7.41 (m, 5H), 4.92-4.99 (m,1H), 4.49 (s, 2H), 4.41-4.47 (m, 1H), 2.63-2.84 (m, 4H).

1-(3-(benzyloxy)cyclobutyl)-5-chloro-4-nitro-1H-pyrazole

To a solution of 1-((1R,3R)-3-(benzyloxy)cyclobutyl)-4-nitro-1H-pyrazole(80 g, 292.73 mmol) in THF (1.6 L) was added LiHMDS (1 M, 567.90 mL)dropwise at −75° C. under N₂ over a period of 1 h. After addition, themixture was stirred for 1 h, then the solution of1,1,1,2,2,2-hexachloroethane (83.16 g, 351.28 mmol) in THF (200 mL) wasadded drop wise at −78° C. The mixture was stirred at −78° C. andstirred for 1 h. The mixture was poured into aqueous NH₄Cl (1.5 L). Theorganic phase was separated and the aqueous phase was extracted withEtOAc (2×500 mL). The combined organic phase was washed with brine (1L), dried with anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=10:1) to afford1-(1R,3R)-3-(benzyloxy)cyclobutyl)-5-chloro-4-nitro-1H-pyrazole as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.29-7.41 (m, 5H),5.16-5.24 (m, 1H), 4.50 (s, 2H), 4.42-4.47 (m, 1H), 2.81-2.89 (m, 2H),2.61-2.70 (m, 2H).

1-(3-(benzyloxy)cyclobutyl)-5-methyl-4-nitro-1H-pyrazole

To a mixture of1-((1R,3R)-3-(benzyloxy)cyclobutyl)-5-chloro-4-nitro-1H-pyrazole (65 g,211.22 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (212.12 g,844.90 mmol, 235.69 mL) and Na₂CO₃ (44.78 g, 422.45 mmol) in 1,4-dioxane(1.5 L) and H₂O (150 mL) was added Pd(dppf)Cl₂.CH₂Cl₂ (27.6 g, 33.80mmol) at 25° C. under N₂. The mixture was then heated to 100° C. andstirred for 40 h. The mixture was cooled to 25° C. and concentratedunder reduced pressure to dryness. The residue was dissolved inPE:EtOAc=2:1 (2 L), then added with anhydrous Na₂SO₄ (100 g), celite(100 g) and stirred for 30 min. The mixture was filtered through a padof celite. The filter cake was washed with PE:EtOAc=2:1 (2×1 L) and thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1)to afford 1(1R,3R)-3-(benzyloxy)cyclobutyl)-5-methyl-4-nitro-1H-pyrazoleas a white solid. LCMS: RT 0.844 min, m/z=288.2 [M+H]⁺.

3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanol

To a solution of1-(1R,3R)-3-(benzyloxy)cyclobutyl)-5-methyl-4-nitro-1H-pyrazole (59.5 g,207.09 mmol) in DCM (1.2 L) was added BCl₃ (1 M, 621.27 mL) dropwise at0° C. under N₂ over a period of 2 h. The mixture was then stirred at 0°C. for 1 h. The mixture was poured into ice-water (600 mL). The aqueousphase was extracted with DCM (2×600 mL). The combined organic phase waswashed with aqueous NaHCO₃ (500 mL), brine (500 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure.(Four batches of the same scale were combined to workup) The residue waspurified by silica gel column chromatography (PE:EtOAc=1:1) to afford(1R,3R)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanol as white solid.¹H NMR (400 MHz, CDCl₃) δ 8.10 (br d, J=4.63 Hz, 1H), 4.98-5.03 (m, 1H),4.70-4.82 (m, 1H), 2.85-2.97 (m, 2H), 2.59-2.66 (m, 3H), 2.47-2.58 (m,2H), 2.38 (br s, 1H).

1-(3-iodocyclobutyl)-5-methyl-4-nitro-1H-pyrazole

To a mixture of (1R,3R)-3-(5-methyl-4-nitro-1H-pyrazol-1-yl)cyclobutanol(70 g, 354.99 mmol), Pph₃ (139.66 g, 532.49 mmol) and imidazole (36.25g, 532.49 mmol) in THF (1.2 L) was added the solution of I₂ (135.15 g,532.49 mmol) in THF (200 mL) dropwise at 0° C. under N₂. After that themixture was stirred at 25° C. for 16 h. The mixture was poured intoice-water (500 mL). The aqueous phase was extracted with EtOAc (2×300mL). The combined organic phase was washed with brine (500 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=10:1) to afford1-((1R,3R)-3-iodocyclobutyl)-5-methyl-4-nitro-1H-pyrazole as whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 4.61-4.83 (m, 1H),4.12-4.34 (m, 1H), 3.09-3.36 (m, 4H), 2.61 (s, 3H).

3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarbonitrile

To a solution of 1-(3-iodocyclobutyl)-5-methyl-4-nitro-pyrazole (2 g,6.51 mmol) in DMF (30 mL) was added KCN (2.5 g, 39.06 mmol) at 0° C.Then the mixture was stirred at 70° C. for 2 days. The mixture wasdiluted with water (60 mL), extracted with EtOAc (4×20 mL). The combinedorganic layers were washed with water (2×50 mL), brine (50 mL), driedover Na₂SO₄, filtered and concentrated. The crude product was purifiedby silica gel column chromatography (PE:EtOAc=1:0 to 1:1) to give3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarbonitrile as a yellowsolid. LCMS: RT 1.066 min, m/z=207.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δppm 8.16 (s, 1H), 5.11 (quin, J=7.81 Hz, 1H), 3.32-3.47 (m, 1H),3.08-3.21 (m, 2H), 2.85-2.95 (m, 2H), 2.67 (s, 3H), 1.59 (s, 1H).

3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutanecarbonitrile

To a mixture of 3-(5-methyl-4-nitro-pyrazol-1-yl)cyclobutanecarbonitrile(200 mg, 969.93 μmol, NH₄Cl (259 mg, 4.85 mmol) in the mixture of EtOH(4.8 mL) and H₂O (1.2 mL) was added Fe (270 mg, 4.85 mmol) at 15° C. Themixture was stirred at 80° C. for 2 h. The mixture was filtered and thefiltrate was concentrated under reduced pressure. The residue wasdiluted with water (10 mL), extracted with EtOAc (10×5 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated to give3-(4-amino-5-methyl-pyrazol-1-yl)cyclobutanecarbonitrile. LCMS: RT 0.101min, m/z=177.2 [M+H]⁺.

2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (70 g,322.61 mmol) in THF (1.4 L) was added a solution of ethanamine (32 g,709.74 mmol, 46.37 mL) in THF (100 mL) dropwise at 0° C. under N₂ over aperiod of 1 h. After addition, the mixture was stirred at 25° C. for 1h. The mixture was filtered and concentrated under reduced pressure toafford a residue. The residue was triturated with DCM (200 mL) andfiltered. The filtrate was recrystallizated with n-heptane (600 mL) andMTBE (400 mL). The precipitated phase was syrup. The liquid wasdiscarded. The syrup residue was purified by silica gel columnchromatography (PE:EtOAc=20:1) to afford2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine as a white solid.¹H NMR (400 MHz, CDCl₃): δ 8.22-8.27 (m, 1H), 5.40 (br s, 1H), 3.56-3.65(m, 2H), 1.29 (t, J=7.22 Hz, 3H). HPLC: RT: 2.68 min.

N4-ethyl-N2-[1-(3-isocyanocyclobutyl)-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of 1-(3-isocyanocyclobutyl)-5-methyl-pyrazol-4-amine (170 mg,964.70 μmol, 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (217mg, 964.70 μmol,), p-TsOH.H₂O (55 mg, 289.41 μmol in 1,4-dioxane (10 mL)was stirred at 90° C. for 2 h. The mixture was concentrated underreduced pressure. The residue was diluted with water (20 mL), extractedwith EtOAc (3×10 mL). The combined organic layers were washed with water(30 mL), brine (30 mL), dried over Na₂SO₄, filtered and concentrated.The crude product was purified by prep-TLC (DCM:MeOH=15:1) to giveN4-ethyl-N2-[1-(3-isocyanocyclobutyl)-5-methyl-pyrazol-4-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine.¹H NMR (400 MHz, CDCl₃) δ ppm 8.10 (s, 1H), 7.65-7.93 (m, 1H), 6.15-6.60(m, 1H), 4.91-5.15 (m, 2H), 3.44-3.55 (m, 2H), 3.23-3.35 (m, 1H),3.07-3.21 (m, 2H), 2.75-2.89 (m, 2H), 2.20 (s, 3H), 1.61 (br s, 1H),1.25 (t, J=7.1 Hz, 3H). HPLC: RT: 1.73 min. MS: m/z=366.2 [M+H]⁺.

Example 2 Synthesis of[9]N4-ethyl-N2-[1-(²H₃))methyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine(34) Ethyl 2-methyl-2-(2H-1,2,3-triazol-2-yl)propanoate

To a mixture of 2H-triazole (20 g, 289.56 mmol) in DMF (200 mL) wasadded t-BuOK (48.74 g, 434.34 mmol) at 0° C. After the addition, ethyl2-bromo-2-methyl-propanoate (78.63 g, 434.34 mmol) was added dropwise at0° C., then the mixture was stirred at 25° C. for 3 h. The mixture waspoured into ice-water (70 mL) and stirred for 5 min. The aqueous phasewas extracted with EtOAc (3×300 mL). The combined organic phase waswashed with brine (2×200 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=3:1) to give ethyl2-methyl-2-(1H-1,2,3-triazol-1-yl)propanoate and isomer ethyl2-methyl-2-(2H-1,2,3-triazol-1-yl)propanoate. LCMS: RT 0.565 min,m/z=184.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.64 (s, 2H), 4.12-4.18(m, 2H), 1.95 (s, 6H), 1.18 (t, J=7.28 Hz, 3H). Undesired isomer, ethyl2-methyl-2-(1H-1,2,3-triazol-1-yl)propanoate. ¹H NMR (400 MHz, CDCl₃): δppm 7.70 (d, J=6.40 Hz, 2H), 4.14-4.19 (m, 2H), 1.94 (s, 6H), 1.20 (t,J=7.28 Hz, 3H).

4-Methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile

To a mixture of MeCN (96.88 mg, 2.36 mmol) in THF (10 mL) was addedn-BuLi (2.5 M, 0.94 mL) dropwise at −78° C. under N₂. After 0.5 h, ethyl2-methyl-2-(2H-1,2,3-triazol-1-yl)propanoate (200 mg, 2.36 mmol) wasadded dropwise over 1 h at −78° C., then the reaction was stirred at−78° C. for 2 h. The mixture was poured into ice-water (20 mL) andstirred for 5 min. The mixture was adjusted to pH=5˜6 by HCl (1 M). Theaqueous phase was extracted with ethyl acetate EtOAc (3×10 mL). Thecombined organic phase was washed with brine (10 mL), dried withanhydrous Na₂SO₄, filtered and concentrated. The residue was purified bysilica gel column chromatography (PE:EtOAc=10:1 to 1:1) to give4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile. LCMS: RT 0.945min, m/z=179.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.76 (s, 1H), 3.11(s, 2H), 1.90 (s, 6H).

1-(²H₃)Methyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine

To a solution of 4-methyl-3-oxo-4-(2H-1,2,3-triazol-2-yl)pentanenitrile(250 mg, 1.4 mmol), trideuteriomethylhydrazine (512.4 mg, 4.2 mmol 2HCl,3 equiv) in EtOH (20 mL) was added dropwise TEA (992 mg, 9.8 mmol, 1.36mL, 7 equiv) at 0° C. After addition, the mixture was stirred at 95° C.for 4 h. The reaction mixture was concentrated to get a residue, whichwas diluted with H₂O (5 mL) and extracted with EtOAc (3×5 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give1-(²H₃)methyl-3-[2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine.LCMS: RT 0.236 min, m/z=210.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm7.61 (s, 1H), 5.25 (s, 1H), 3.39 (br s, 1H), 2.05 (s, 3H).

N4-Ethyl-N2-[1-(²H₃)methyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of1-(²H₃)methyl-3-[2-(2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-amine(100 mg, 477.85 μmol) and2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (107.8 mg, 477.85μmol) in 1,4-dioxane (10 mL) was added p-TsOH (24.69 mg, 143.36 μmol).The mixture was stirred at 90° C. for 3 h. The reaction mixture wasconcentrated under reduced pressure. The residue was diluted with H₂O (5mL) and adjusted to pH=8-9 with aq. NaHCO₃ and extracted with EtOAc (3×8mL). The combined organic layers were washed with brine (10 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (PE:EtOAc=1:1) and trituration withn-heptane to giveN4-ethyl-N2-[1-(²H₃)methyl-3-[2H-1,2,3-triazol-2-yl)propan-2-yl]-1H-pyrazol-5-yl]-5-(trifluoromethyl)pyrimidine-2,4-diamine.¹H NMR (400 MHz, CDCl₃): δ ppm 8.10 (s, 1H), 7.62 (s, 2H), 6.73 (br s,1H), 6.03 (s, 1H), 5.15 (br s, 1H), 3.35-3.44 (m, 2H), 2.11 (s, 6H),1.18-1.21 (t, J=7.28 Hz, 3H). HPLC: RT 2.24 min, m/z: 399.2 [M+H]⁺.

Example 3 Synthesis ofN2-[2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(78) 4-methyl-3-oxo-4-(triazol-2-yl)pentanenitrile

To a mixture of 2H-triazole (20 g, 289.56 mmol) in DMF (200 mL) wasadded t-BuOK (48.74 g, 434.34 mmol) in one portion at 0° C. under N₂.After addition, methyl 2-bromo-2-methyl-propanoate (78.63 g, 434.34mmol, 56.16 mL) was added dropwise. The mixture was stirred at 25° C.for 3 h. The residue was poured into ice-water (700 mL) and stirred for5 min. The aqueous phase was extracted with EtOAc (3×300 mL). Thecombined organic phase was washed with brine (2×100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 3:1) to give methyl 2-methyl-2-(triazol-2-yl)propanoate as a yellowoil. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.649 (s, 2H), 3.701 (s, 3H), 1.963(s, 6H).

4-methyl-3-oxo-4-(triazol-2-yl)pentanenitrile

To a solution of CH₃CN (485.21 mg, 11.82 mmol) in THF (20 mL) was addeddropwise n-BuLi (2.5 M, 4.73 mL) at −78° C. over 10 min. After addition,the mixture was stirred at this temperature for 50 min, and then methyl2-methyl-2-(triazol-2-yl)propanoate (1 g, 5.91 mmol) was added dropwiseat −78° C. The resulting mixture was stirred at −78° C. for 2 h. Thereaction mixture was poured into ice-water (50 mL), adjusted to pH=5-6with HCl (1N) and extracted with EtOAc (3×20 mL). The combined organiclayers were washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=10:1 to 1:1) to give4-methyl-3-oxo-4-(triazol-2-yl)pentanenitrile as a yellow solid. ¹H NMR(400 MHz, CDCl₃): δ ppm 7.761 (s, 2H), 3.106 (s, 2H), 1.904 (s, 6H).

2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-amine

To a mixture of 4-methyl-3-oxo-4-(triazol-2-yl)pentanenitrile (400 mg,2.24 mmol) and cyclopropylhydrazine dihydrochloride (974.6 mg, 6.72mmol) in EtOH (10 mL) was added HCl (12 M, 560 μL) at 25° C. under N₂.The mixture was stirred at 90° C. for 12 h. The mixture wasconcentrated. The residue was poured into aq. NaHCO₃ (10 mL) and stirredfor 5 min. The aqueous phase was extracted with EtOAc (3×5 mL). Thecombined organic phase was dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (PE:EtOAc=1/1) to give2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-amine as ayellow oil. ¹H NMR: (400 MHz, CDCl₃): δ ppm 7.756-7.722 (d, J=13.6 Hz,1H), 7.616 (s, 1H), 2.041 (s, 6H), 1.139˜1.100 (m, 2H), 1.022-1.004 (m,2H).

N2-[2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

A mixture of2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-amine (77 mg,331.5 μmol), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine(74.79 mg, 331.5 μmol) and p-TsOH.H₂O (31.53 mg, 165.75 μmol) in1,4-dioxane (10 mL) was stirred at 90° C. for 3 h under N₂. The reactionmixture was quenched by sat. NaHCO₃ (10 mL) and extracted with EtOAc(2×10 mL). The combined organic layers were washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) and furtherpurification by prep-HPLC (FA) to giveN2-[2-cyclopropyl-5-[1-methyl-1-(triazol-2-yl)ethyl]pyrazol-3-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.¹H NMR (400 MHz, CDCl₃): δ 8.13 (s, 1H), 7.62 (s, 2H), 7.30 (br s, 1H),6.13 (s, 1H), 5.18 (br s, 1H), 3.38-3.47 (m, 2H), 3.24 (tt, J=3.59, 6.95Hz, 1H), 2.10 (s, 6H), 1.24 (t, J=7.22 Hz, 3H), 1.09-1.21 (m, 4H). HPLC:RT 2.61 min. MS: m/z: 422.3 [M+H]⁺.

Example 4 Synthesis of (3S)- and(3R)-3-[1-cyclopropyl-5-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-3-yl]-3-methyl-tetrahydrofuran-2-one(143 and 144) Tert-butyl N-(1-methylcyclopropyl)carbamate

To a mixture of sodium (5.34 g, 232.32 mmol) in diethyl carbonate (50mL) was added a solution of tetrahydrofuran-2-one (20 g, 232.32 mmol) indiethyl carbonate (25 mL) at 100° C. over a period of 3 h. The mixturewas cooled to 20° C. and quenched by ice sat. NH₄Cl, then adjusted topH=5 by adding 1N HCl. The aqueous phase was extracted with EtOAc (3×30mL). The combined organic phase was washed with brine (2×20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=10:1 to 0:1) to give ethyl 2-oxotetrahydrofuran-3-carboxylateas a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.49 (td, J=8.47,5.52 Hz, 1H), 4.34 (dt, J=8.69, 7.45 Hz, 1H), 4.24-4.30 (m, 2H), 3.55(dd, J=9.35, 7.59 Hz, 1H), 2.69 (dq, J=13.07, 7.57 Hz, 1H), 2.51 (dddd,J=13.08, 9.32, 7.59, 5.52 Hz, 1H), 1.32 (t, J=7.09 Hz, 3H).

Ethyl 3-methyl-2-oxo-tetrahydrofuran-3-carboxylate

To a solution of ethyl 2-oxotetrahydrofuran-3-carboxylate (6.9 g, 43.63mmol) in THF (150 mL) was added NaH (1.92 g, 47.99 mmol, 60% purity) at0° C. over 30 min. After addition, the mixture was stirred at 20° C. for30 min, and then MeI (9.29 g, 65.45 mmol, 4.07 mL) was added dropwise at0° C. over 30 min. The resulting mixture was stirred at 20° C. for 10.5h. The reaction mixture was poured into aqueous sat. NH₄Cl solution at0° C. and extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine (30 mL), dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bysilica gel column chromatography (PE:EtOAc=20:1 to 1:1) to give ethyl3-methyl-2-oxo-tetrahydrofuran-3-carboxylate as a yellow oil. ¹H NMR(400 MHz, CDCl₃): δ ppm 4.32-4.44 (m, 2H) 4.24 (q, J=7.20 Hz, 2H), 2.76(ddd, J=13.01, 7.06, 4.19 Hz, 1H), 2.20 (dt, J=13.23, 8.38 Hz, 1H), 1.54(s, 3H), 1.30 (t, J=7.17 Hz, 3H).

3-(3-methyl-2-oxo-tetrahydrofuran-3-yl)-3-oxo-propanenitrile

To a solution of CH₃CN (1.2 g, 30.03 mmol, 1.58 mL) in THF (50 mL) wasadded dropwise n-BuLi (12.01 mL, 2.5 M) at −78° C. over 30 min under N₂.After addition, the mixture was stirred at this temperature for 30 min.The suspension mixture was added dropwise to a solution of ethyl3-methyl-2-oxo-tetrahydrofuran-3-carboxylate (4.7 g, 27.30 mmol) in THF(50 mL) at −78° C. for 30 min. The resulting mixture was warmed to −40°C. and stirred at −40° C. for 1.5 h. The reaction mixture was quenchedby addition of sat. NH₄Cl at 0° C., and then adjusted to pH=4-5 with 1NHCl and extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give3-(3-methyl-2-oxo-tetrahydrofuran-3-yl)-3-oxo-propanenitrile as a yellowsolid, which was used in next step without further purification. ¹H NMR(400 MHz, CDCl₃): δ ppm 4.29-4.46 (m, 2H), 3.79-4.12 (m, 2H), 3.03 (ddd,J=13.40, 7.55, 6.17 Hz, 1H), 2.10 (dt, J=13.73, 7.14 Hz, 1H), 1.60 (s,3H).

3-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-methyl-tetrahydrofuran-2-one

A mixture of3-(3-methyl-2-oxo-tetrahydrofuran-3-yl)-3-oxo-propanenitrile (200 mg,1.2 mmol) and cyclopropylhydrazine dihydrochloride salt (174 mg, 1.2mmol) in i-PrOH (5 mL) was stirred at 50° C. for 16 h under N₂. Thereaction solution was adjusted to pH=7 with sat. NaHCO₃, extracted withEtOAc (3×5 mL). The organic layers were combined, washed with brine (5mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The crude product was purified by prep-TLC(DCM:MeOH=10:1) to give3-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-methyl-tetrahydrofuran-2-one asa yellow oil. ¹H NMR (400 MHz, CDCl₃): δ ppm 5.47 (s, 1H), 4.24-4.41 (m,2H), 3.76-3.94 (br, 2H), 3.04-3.14 (m, 1H), 2.89-3.02 (m, 1H), 2.12-2.28(m, 1H), 1.53 (s, 3H), 0.95-1.04 (m, 4H).

(3S) and (3R)N2-[5-cyclopropyl-1-[3-(triazol-2-yl)cyclobutyl]pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of3-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-methyl-tetrahydrofuran-2-one(90 mg, 406.76 μmol in 1,4-dioxane (5 mL) was added2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (91.77 mg, 406.76μmol and p-TsOH (14.01 mg, 81.35 μmol. The mixture was stirred at 90° C.for 10 h. The reaction solution was adjusted to pH=7 with sat.NaHCO₃,extracted with EtOAc (3×5 mL). The organic layers were combined, washedwith brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude product was purified byprep-TLC (PE:EtOAc=1:1) to give a mixtures of enantiomers, which wereseparated by SFC.

First Eluting Isomer:

¹H NMR (400 MHz, CDCl₃): δ ppm 8.09 (s, 1H), 7.16 (br s, 1H), 6.55 (s,1H), 5.17 (br s, 1H), 4.20-4.32 (m, 2H), 3.48-3.57 (m, 2H), 3.12-3.20(m, 1H), 2.93 (ddd, J=12.58, 6.49, 4.02 Hz, 1H), 2.19 (dt, J=12.58, 8.52Hz, 1H), 1.53 (s, 3H), 1.24 (t, J=7.22 Hz, 3H), 1.02-1.13 (m, 4H). HPLC:RT: 2.33 min. MS: m/z: 411.2 [M+H]⁺.

Second Eluting Isomer:

¹H NMR (400 MHz, CDCl₃): δ ppm 8.17 (d, J=0.75 Hz, 1H), 7.28 (br s, 1H),6.62 (s, 1H), 5.26 (br s, 1H), 4.28-4.42 (m, 2H), 3.55-3.66 (m, 2H),3.17-3.28 (m, 1H), 3.01 (ddd, J=12.61, 6.46, 4.02 Hz, 1H), 2.26 (dt,J=12.55, 8.47 Hz, 1H), 1.53-1.64 (m, 3H), 1.32 (t, J=7.22 Hz, 3H),1.10-1.21 (m, 5H). HPLC: RT: 2.33 min. MS: m/z: 411.2 [M+H]⁺.

Example 5 Synthesis of1-(1-cyclopropyl-5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-3-yl)pyrrolidin-2-one(153) 1-cyclopropyl-1H-pyrazole-3,5-diamine

A mixture of propanedinitrile (6.15 g, 93.09 mmol) andcyclopropylhydrazine (9 g, 62.06 mmol, 2HCl salt) in i-PrOH (10 mL) washeated at 105° C. for 5 h. The reaction solution was cooled to 0° C.,adjusted to pH=7 with sat. NaHCO₃, concentrated under reduced pressure.The crude product was purified by silica gel column chromatography(DCM:MeOH=30:1 to 10:1) to give 1-cyclopropylpyrazole-3,5-diamine as abrown syrup. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.88 (s, 1H), 3.80 (br s,2H), 2.98 (tt, J=6.89, 3.47 Hz, 1H), 2.84 (br s, 2H), 1.05 (dq, J=7.86,3.70 Hz, 2H), 0.93-1.00 (m, 2H).

N-(5-amino-1-cyclopropyl-1H-pyrazol-3-yl)-4-chlorobutanamide

To a solution of 1-cyclopropylpyrazole-3,5-diamine (2.25 g, 16.28 mmol)and TEA (3.29 g, 32.56 mmol) in DCM (200 mL) was added dropwise4-chlorobutanoyl chloride (2.07 g, 14.65 mmol) at 0° C. for 30 min. Themixture was stirred at 0° C. for 30 min and stirred at 15° C. for 1 h.The reaction mixture was diluted with H₂O (50 mL) and extracted withDCM:i-PrOH (V:V=3:1, 3×30 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 0:1) to giveN-(5-amino-1-cyclopropyl-pyrazol-3-yl)-4-chloro-butanamide as a yellowoil. ¹H NMR (400 MHz, CDCl₃): δ ppm 7.97 (br s, 1H), 5.94 (s, 1H), 3.90(br s, 2H), 3.63 (t, J=6.21 Hz, 2H), 3.08 (tt, J=6.82, 3.59 Hz, 1H),2.49 (t, J=7.09 Hz, 2H), 2.16 (quin, J=6.62 Hz, 2H), 0.93-1.13 (m, 4H).

1-(5-amino-1-cyclopropyl-1H-pyrazol-3-yl)pyrrolidin-2-one

To a solution ofN-(5-amino-1-cyclopropyl-pyrazol-3-yl)-4-chloro-butanamide (1.3 g, 5.36mmol) in THF (390 mL) was added NaH (536 mg, 13.40 mmol, 60% purity) at0° C. over 10 min. After addition, the mixture was stirred at 0° C. for20 min, and then stirred at 15° C. for 1.5 h. The reaction mixture wasquenched by addition of aq. NH₄Cl (100 mL) at 0° C., and then extractedwith DCM:i-PrOH (V:V=3:1, 3×100 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=10:1to 0:1) to give 1-(5-amino-1-cyclopropyl-pyrazol-3-yl)pyrrolidin-2-oneas an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ ppm 6.10 (s, 1H), 3.89(t, J=7.06 Hz, 4H), 3.10 (tt, J=6.86, 3.61 Hz, 1H), 2.52 (t, J=8.05 Hz,2H), 2.11 (quin, J=7.61 Hz, 2H), 1.06-1.12 (m, 2H), 1.00-1.06 (m, 2H).

1-(1-cyclopropyl-5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-3-yl)pyrrolidin-2-one

To a solution of 1-(5-amino-1-cyclopropyl-pyrazol-3-yl)pyrrolidin-2-one(180 mg, 872.77 μmol and2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (197 mg, 872.77μmol in 1,4-dioxane (10 mL) was added p-TsOH.H₂O (45 mg, 261.83 μmol.The mixture was stirred at 90° C. for 12 h. The reaction mixture wasdiluted with H₂O (30 mL) and adjusted to pH=8-9 with aq. NaHCO₃ (10 mL)at 0° C. and extracted with EtOAc (3×30 mL). The combined organic layerswere washed with brine (10 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (FA) to give1-(1-cyclopropyl-5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-3-yl)pyrrolidin-2-one.¹H NMR (400 MHz, CDCl₃): δ ppm 8.16 (s, 1H), 7.35 (br s, 1H), 7.22 (s,1H), 5.27 (br s, 1H), 3.93 (t, J=7.06 Hz, 2H), 3.62-3.73 (m, 2H),3.19-3.27 (m, 1H), 2.56 (t, J=8.16 Hz, 2H), 2.09-2.20 (m, 2H), 1.34 (t,J=7.28 Hz, 3H), 1.15-1.20 (m, 2H), 1.09-1.15 (m, 2H). HPLC: RT 2.11 min.MS: m/z: 396.2 [M+H]⁺.

Example 6 Synthesis ofN2-[3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(110) 3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)thietane 1,1-dioxide

To a mixture of 3-cyclopropyl-4-nitro-1H-pyrazole (500 mg, 3.26 mmol) inDMF (15 mL) was added NaH (156 mg, 3.91 mmol, 60% purity) at 0° C. underN₂. The mixture was stirred at 20° C. for 30 min, then treated with3-bromothietane 1,1-dioxane (1.01 g, 3.26 mmol) and stirred at 20° C.for 15.5 h. The mixture was poured into ice-water (30 mL) and extractedwith EtOAc (3×15 mL). The combined organic phase was washed with brine(3×15 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=1:0 to 3:1), to give3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)thietane 1,1-dioxide as a yellowoil.

3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-amine

To a solution of 3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)thietane1,1-dioxide (160 mg, 621.91 μmol in EtOH (8 mL) and H₂O (2 mL) was addedFe (174 mg, 3.11 mmol) and NH₄Cl (166 mg, 3.11 mmol, 108.71 μL) at 20°C. The reaction mixture was heated at 70° C. for 2 h, then concentratedunder reduced pressure. The residue was washed with a mixture solvent ofDCM and MeOH (10 mL, 10:1), filtered and the filtrate was concentratedunder reduced pressure to give3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-amine as a brown oil.

N2-[3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a solution of 3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-amine(100 mg, 439.99 μmol and2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (99 mg, 439.99μmol in 1,4-dioxane (5 mL) was added p-TsOH (15 mg, 88 μmol. Thereaction solution was stirred at 80° C. for 1 h. The mixture wasadjusted to pH=7 with sat.NaHCO₃, extracted with EtOAc (3×5 mL). Thecombined organic layers were washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude product was purified by prep-HPLC (neutral) to giveN2-[3-cyclopropyl-1-(1,1-dioxothietan-3-yl)pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 1H), 8.12 (br s, 1H), 6.62-7.03 (m,1H), 5.15 (br s, 1H), 5.07 (br s, 1H), 4.66 (br s, 2H), 4.58 (br s, 2H),3.58 (br d, J=5.90 Hz, 2H), 1.67-1.78 (m, 1H), 1.32 (br t, J=6.78 Hz,3H), 0.91-0.98 (m, 2H), 0.81-0.90 (m, 2H). HPLC: RT: 1.92 min. MS:m/z=417.2 [M+H]⁺.

Example 7 Synthesis of(1R,5S)-1-[1-cyclopropyl-5-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-3-yl]-3-oxabicyclo[3.1.0]hexan-2-one(162) Methyl (1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate

Na (8.27 g, 359.52 mmol) was added into MeOH (500 mL) and the mixturewas stirred at 20° C. for 3 h until the Na dissolved. Dimethylpropanedioate (50 g, 378.44 mmol) was added at 0° C., after 30 min,(2S)-2-(chloromethyl)oxirane (31.51 g, 340.6 mmol) was added at 20° C.under N₂. The mixture was stirred at 90° C. for 12 h. The mixture wasconcentrated under reduced pressure at 45° C. The residue was pouredinto ice-water (100 mL) and stirred for 5 min. The aqueous phase wasextracted with EtOAc (3×300 mL). The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=100:1 to 5:1) to give methyl(1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate as an oil. ¹H NMR(400 MHz, CDCl₃): δ ppm 4.35 (dd, J=9.37, 4.74 Hz, 1H), 4.18 (d, J=9.48Hz, 1H), 3.79 (s, 3H), 3.33-3.40 (m, 1H), 2.74 (dt, J=7.94, 5.18 Hz,1H), 2.07 (dd, J=7.94, 4.85 Hz, 1H), 1.39 (t, J=5.07 Hz, 1H).

3-oxo-3-[(1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexan-1-yl)]propanenitrile

To a mixture of MeCN (1.45 g, 35.22 mmol) in THF (20 mL) was addedn-BuLi (2.5 M, 14.09 mL) at −78° C. under N₂. After 1 h the mixture wasadded into the solution of methyl(1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (5 g, 32.02 mmol)in THF (30 mL) at −78° C., then the mixture was stirred at −78° C. for 2h. The mixture was poured into aq. NH₄Cl (30 mL) and stirred for 5 minand adjusted the pH=3 with diluted HCl (1N). The aqueous phase wasextracted with EtOAc (3×30 mL). The combined organic phase was washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:MTBE=50:1 to 0:1) to give 3-oxo-3-[(1R,5S)-2-oxo-3-oxabicyclo [3.1.0] hexan-1-yl] propanenitrile as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ ppm 4.25-4.47 (m, 3H), 4.03-4.15 (m,1H), 3.02 (dt, J=7.99, 5.26 Hz, 1H), 2.19 (dd, J=8.16, 4.41 Hz, 1H),1.58-1.65 (m, 1H).

(1R,5S)-1-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-oxabicyclo[3.1.0]hexan-2-one

To a mixture of3-oxo-3-[(1R,5S)-2-oxo-3-oxabicyclo[3.1.0]hexan-1-yl]propanenitrile (800mg, 4.84 mmol) in i-PrOH (20 mL) was added cyclopropylhydrazinedihydrochloride salt (632.28 mg, 4.36 mmol) in one portion at 25° C.under N₂. The mixture was stirred at 50° C. for 12 h. The mixture waspoured into aq. NaHCO₃ (50 mL) and stirred for 10 min. The aqueous phasewas extracted with DCM/MeOH (3:1, 3×20 mL). The combined organic phasewas washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, DCM:MeOH=20:1) to give(1R,5S)-1-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-oxabicyclo[3.1.0]hexan-2-oneas a brown oil. LCMS: RT 0.370 min, m/z=220.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ ppm 5.76 (s, 1H), 4.38 (dd, J=9.15, 4.74 Hz, 1H), 4.20 (d,J=9.26 Hz, 1H), 3.83 (br s, 2H), 3.06 (tt, J=6.89, 3.58 Hz, 1H), 2.61(dt, J=7.72, 4.63 Hz, 1H), 1.81 (dd, J=7.72, 4.41 Hz, 1H), 1.24 (t,J=4.74 Hz, 1H), 0.94-1.11 (m, 4H).

(1R,5S)-1-[1-cyclopropyl-5-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-3-yl]-3-oxabicyclo[3.1.0]hexan-2-one

To a mixture of(1R,5S)-1-(5-amino-1-cyclopropyl-pyrazol-3-yl)-3-oxabicyclo[3.1.0]hexan-2-one(150 mg, 684.18 μmol) and2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (154.35 mg, 684.18μmol) in 1,4-dioxane (5 mL) was added p-TsOH.H₂O (26.03 mg, 136.84 μmol)in one portion at 20° C. under N₂. The mixture was stirred at 90° C. for12 h. The mixture was poured into aq. NaHCO₃ (30 mL) and stirred for 10min. The aqueous phase was extracted with EtOAc (3×20 mL). The combinedorganic phase was washed with brine (30 mL), dried with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-HPLC (neutral condition) to give(1R,5S)-1-[1-cyclopropyl-5-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-3-yl]-3-oxabicyclo[3.1.0]hexan-2-one.¹H NMR (400 MHz, CDCl₃): δ ppm 8.10 (s, 1H), 7.13 (br s, 1H), 6.87 (s,1H), 5.16 (br s, 1H), 4.35 (dd, J=9.22, 4.71 Hz, 1H), 4.18 (d, J=9.29Hz, 1H), 3.49-3.64 (m, 2H), 3.07-3.19 (m, 1H), 2.57-2.68 (m, 1H), 1.81(dd, J=7.72, 4.45 Hz, 1H), 1.22-1.30 (m, 4H), 0.98-1.12 (m, 3H), 1.09(br s, 1H). HPLC: reaction time: 2.17 min. MS: m/z: 409 [M+H]⁺.

Example 8 Synthesis of(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarbonitrile(181) 3-[2-(3-benzyloxycyclobutylidene)hydrazino]propanenitrile

A mixture of 3-benzyloxycyclobutanone (10 g, 56.75 mmol) and3-hydrazinopropanenitrile (4.83 g, 56.75 mmol) in EtOH (150 mL) wasstirred at 20° C. for 16 h. The mixture was concentrated under reducedpressure to afford3-[2-(3-benzyloxycyclobutylidene)hydrazino]propanenitrile (13.81 g,crude) as a yellow oil. LCMS: RT 0.686 min, m/z=244.2 [M+H]⁺.

2-(3-benzyloxycyclobutyl)pyrazol-3-amine

To a mixture of3-[2-(3-benzyloxycyclobutylidene)hydrazino]propanenitrile (13.81 g,56.76 mmol) in t-BuOH (130 mL) was added t-BuONa (5.45 g, 56.76 mmol)under N₂. The mixture was stirred at 110° C. for 3 h. The mixture waspoured into ice-water (100 mL) and extracted with EtOAc (2×100 mL). Theorganic phase was adjusted to pH=3 by 2N HCl and washed with water(3×100 mL). The aqueous phase was adjusted to pH=8 by 6 N NaOH,extracted with EtOAc (3×100 mL), washed with brine (100 mL), dried overanhydrous Na₂SO₄, filtered and concentrated to afford2-(3-benzyloxycyclobutyl)pyrazol-3-amine as a yellow oil. LCMS: RT 0.625min, m/z=244.2 [M+H]⁺.

3-(5-aminopyrazol-1-yl)cyclobutanol

To a solution of 2-(3-benzyloxycyclobutyl)pyrazol-3-amine (5 g, 20.55mmol) in DCM (200 mL) was added BCl₃ (1 M, 8.02 mL) at 0° C. under N₂.The mixture was stirred at 20° C. for 2 h. The mixture was poured intosaturated NaHCO₃ (200 mL) and the aqueous phase was concentrated underreduced pressure. The residue was washed with DCM:MeOH (v:v=10:1, 100mL), filtered and the filtrate was concentrated under reduced pressureto afford 3-(5-aminopyrazol-1-yl)cyclobutanol as a yellow oil. LCMS: RT0.096 min, m/z=154.1 [M+H]⁺.

(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanoland(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanol

To a mixture of 3-(5-aminopyrazol-1-yl)cyclobutanol (2.2 g, 14.36 mmol)in NMP (22 mL) was added2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (2.59 g, 11.49mmol) and p-TsOH.H₂O (819.59 mg, 4.31 mmol) in one portion at 20° C.under N₂. The mixture was then heated to 100° C. and stirred for 16 h.The mixture was cooled to 20° C., poured into water (150 mL) andadjusted to pH=7-8 by aqueous NaHCO₃. The aqueous phase was extractedwith EtOAc (3×50 mL). The combined organic phase was washed with brine(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by silicagel column chromatography (DCM:MeOH=30:1) to afford a mixture of(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanoland(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanolas a yellow gum.

(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate

To a mixture of(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanoland(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutano(2 g, 5.84 mmol) in DCM (40 mL) was added TEA (709.14 mg, 7.01 mmol) andMsCl (802.77 mg, 7.01 mmol) at 0° C. under N₂. The mixture was thenstirred at 0° C. for another 1 h. The mixture was added with water (10mL) and stirred for 3 min. The organic phase was separated, washed withbrine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bysilica gel column chromatography (DCM:MeOH=30:1) to afford a mixture of(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate and(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate as a yellow oil.

(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarbonitrile

To a mixture of(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate and(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate (200 mg, 475.73 μmol) in DMSO (4 mL) was added18-crown-6 (12 mg, 47.57 ρmol) and NaCN (140 mg, 2.85 mmol) at 20° C.under N₂. The mixture was then heated to 120° C. and stirred for 8 h.The mixture was cooled to 20° C. and poured into water (50 mL). Theaqueous phase was extracted with EtOAc (3×20 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by prep-HPLC (FA) to give product, which wasfurther purified by prep-TLC (PE:EtOAc=1:1) to afford(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarbonitrileand a byproduct2-(6,7-dihydro-5,7-methanopyrazolo[1,5-a]pyrimidin-4(5H)-yl)-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine.

(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutanecarbonitrile

¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.57 (d, J=1.76 Hz, 1H), 7.08(br s, 1H), 6.19 (d, J=1.76 Hz, 1H), 5.16 (br s, 1H), 5.06 (quin, J=7.87Hz, 1H), 3.36-3.48 (m, 2H), 3.24-3.36 (m, 1H), 3.06-3.18 (m, 2H),2.73-2.84 (m, 2H), 1.20 (t, J=7.22 Hz, 3H). LCMS: RT: 0.652 min. MS:m/z: 352.1 [M+H]⁺.

Example 9 Synthesis ofN2-(1-((1r,3r)-3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(182) andN2-(1-((1r,3r)-3-(1H-1,2,3-triazol-1-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(183)N2-(1-((1R,3R)-3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamineandN2-(1-((1R,3R)-3-(1H-1,2,3-triazol-1-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a mixture of(1S,3S)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate and(1R,3R)-3-(5-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)cyclobutylmethanesulfonate (300 mg, 713.59 μmol in DMF (5 mL) was added K₂CO₃ (148mg, 1.07 mmol) and 2H-triazole (74 mg, 1.07 mmol) in one portion at 20°C. under N₂. The mixture was then heated to 120° C. and stirred for 8 h.The mixture was cooled to 20° C. and poured into water (50 mL). Theaqueous phase was extracted with EtOAc (3×20 mL). The combined organicphase was washed with brine (20 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue wasseparated by prep-HPLC (FA condition) to affordN2-(1-(1R,3R)-3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamineandN2-(1-(1R,3R)-3-(1H-1,2,3-triazol-1-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.

N2-(1-((1R,3R)-3-(2H-1,2,3-triazol-2-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(182)

¹H NMR (400 MHz, CDCl₃): δ 8.11 (s, 1H), 7.64 (s, 2H), 7.61 (d, J=1.88Hz, 1H), 6.83 (br s, 1H), 6.29 (d, J=1.76 Hz, 1H), 5.50 (tt, J=4.49,8.69 Hz, 1H), 5.17-5.27 (m, 1H), 5.13 (br s, 1H), 3.39-3.51 (m, 2H),3.25-3.36 (m, 2H), 3.01-3.14 (m, 2H), 1.21 (t, J=7.22 Hz, 3H). LCMS: RT:0.706 min. MS: m/z: 394.3 [M+H]⁺.

N2-(1-((1R,3R)-3-(1H-1,2,3-triazol-1-yl)cyclobutyl)-1H-pyrazol-5-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(183)

¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=1.63Hz, 1H), 7.60 (s, 1H), 6.70 (br s, 1H), 6.28 (d, J=1.76 Hz, 1H),5.36-5.45 (m, 1H), 5.18-5.27 (m, 1H), 5.14 (br s, 1H), 3.37-3.53 (m,2H), 3.31 (ddd, J=5.77, 8.31, 13.65 Hz, 2H), 3.11-3.23 (m, 2H), 1.22 (t,J=7.22 Hz, 3H). LCMS: RT: 0.660 min. MS: m/z: 394.2 [M+H]⁺.

Example 10 Synthesis ofN2-(5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(105) 2-(4-nitropyrazol-1-yl)pyrazine

To a solution of 4-nitro-1H-pyrazole (1 g, 8.84 mmol) in DMF (20 mL) wasadded NaH (424 mg, 10.61 mmol, 60% purity) at 0° C. under N2. Themixture was stirred at 0° C. for 1 h. Then 2-chloropyrazine (1.01 g,8.84 mmol, 790.99 μL) was added at 0° C. and the mixture was heated to80° C. and stirred for 12 h. The mixture was cooled to 20° C., quenchedby cold aqueous sat. NH₄Cl solution (60 mL). The aqueous phase wasextracted with EtOAc (3×20 mL). The combined organic phase was washedwith brine (3×15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=10:1 to 0:1) to give2-(4-nitropyrazol-1-yl)pyrazine as a light-yellow solid. 1H NMR (400MHz, DMSO-d6): δ ppm 9.54 (s, 1H), 9.31 (d, J=1.13 Hz, 1H), 8.81 (d,J=2.51 Hz, 1H), 8.70-8.74 (m, 1H), 8.71 (s, 1H), 8.69 (dd, J=2.45, 1.32Hz, 1H).

2-(5-chloro-4-nitro-pyrazol-1-yl)pyrazine

To a solution of 2-(4-nitropyrazol-1-yl)pyrazine (0.78 g, 4.08 mmol) inTHF (15 mL) was added LiHMDS (1 M, 4.49 mmol, 4.49 mL) at −78° C. underN₂. The mixture was stirred at −78° C. for 30 min, then a solution of1,1,1,2,2,2-hexachloroethane (1.06 g, 4.49 mmol, 508.45 μL) in THF (10mL) was added at −78° C. under N₂ and the mixture was stirred for 3.5 h.The mixture was quenched by cold aqueous sat. NH₄Cl (30 mL). The aqueousphase was extracted with EtOAc (3×10 mL). The combined organic phase waswashed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1 to 1:1) to give2-(5-chloro-4-nitro-pyrazol-1-yl)pyrazine as a white solid. LCMS: RT1.066 min. MS m/z=226.0 [M+H]⁺.

2-(5-cyclopropyl-4-nitro-pyrazol-1-yl)pyrazine

To a mixture of 2-(5-chloro-4-nitro-pyrazol-1-yl)pyrazine (200 mg,886.56 μmol and cyclopropylboronic acid (380 mg, 4.43 mmol) in1,4-dioxane (10 mL) was added KF (154 mg, 2.66 mmol) andPd(dppf)Cl₂.CH₂C₂ (145 mg, 177.31 μmol at 20° C. under N₂. The mixturewas heated to 110° C. and stirred for 12 h. The mixture was cooled to20° C. and filtered. The residue was added with water (15 mL). Theaqueous phase was extracted with EtOAc (3×8 mL). The combined organicphase was washed with brine (8 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=10:1 to 0:1) to give2-(5-cyclopropyl-4-nitro-pyrazol-1-yl)pyrazine. 1H NMR (400 MHz, CDCl₃):δ ppm 9.08 (s, 1H), 8.71 (d, J=2.38 Hz, 1H), 8.56-8.61 (m, 1H), 8.29 (s,1H), 2.36 (tt, J=8.52, 5.79 Hz, 1H), 1.07-1.17 (m, 2H), −0.17 (tt,J=8.96, 5.91 Hz, 2H).

5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-amine

To a solution of 2-(5-cyclopropyl-4-nitro-pyrazol-1-yl)pyrazine (240 mg,1.04 mmol) in EtOH (16 mL) and H₂O (4 mL) was added NH₄Cl (277 mg, 5.19mmol) and Fe (290 mg, 5.19 mmol) at 20° C. The mixture was heated to 80°C. and stirred for 2 h. The mixture was cooled to 20° C., filtered andconcentrated under reduced pressure. The residue was washed withDCM:MeOH (10 mL, v:v=10:1), filtered and concentrated under reducedpressure to give 5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-amine as a brownoil. LCMS: RT 0.711 min. MS m/z=202.1 [M+H]⁺.

N2-(5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a mixture of 5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-amine (100 mg,496.95 μmol) and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine(112 mg, 496.95 μmol in 1,4-dioxane (5 mL) was added p-TsOH.H₂O (34 mg,198.78 μmol) at 20° C. The mixture was heated to 90° C. and stirred for2 h. The mixture was cooled to 20° C., added with water (10 mL) andadjusted to pH=7-8 by sat. NaHCO₃. The aqueous phase was extracted withEtOAc (3×8 mL). The combined organic phase was washed with brine (2×5mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas purified by silica gel column chromatography (PE:EtOAc=10:1 to 0:1)to giveN₂-(5-cyclopropyl-1-pyrazin-2-yl-pyrazol-4-yl)-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.¹H NMR (400 MHz, MeOD): δ ppm 9.08 (s, 1H), 8.55 (s, 2H), 8.04 (br s,2H), 3.53 (q, J=6.82 Hz, 2H), 2.16-2.34 (m, 1H), 1.20 (br t, J=7.03 Hz,3H), 0.91 (br d, J=6.90 Hz, 2H), 0.55 (br d, J=4.77 Hz, 2H). HPLC: RT:2.06 min. MS: m/z: 391.2 [M+H]⁺.

Example 11 Synthesis of(3S)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-3-methyl-tetrahydrofuran-2-oneand(3R)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-3-methyl-tetrahydrofuran-2-one(113 and 122)3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one

To a solution of 3-cyclopropyl-4-nitro-1H-pyrazole (1 g, 6.53 mmol) inDMF (10 mL) was added NaH (313 mg, 7.84 mmol, 60% purity) at 0° C. underN₂. The mixture was stirred at 20° C. for 30 min, then treated with3-bromotetrahydrofuran-2-one (1.19 g, 7.18 mmol, 670 μL) and stirred for15.5 h. The mixture was poured into ice-water (20 mL) and extracted withEtOAc (3×10 mL). The combined organic phase was washed with brine (3×10mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=1:0 to 1:1) to give3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one as a yellowoil. ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 4.96 (t, J=9.16 Hz, 1H),4.65 (td, J=8.88, 3.45 Hz, 1H), 4.39-4.51 (m, 1H), 2.95 (dq, J=13.25,8.92 Hz, 1H), 2.77-2.87 (m, 1H), 2.56-2.65 (m, 1H), 1.01-1.09 (m, 2H),0.93-1.01 (m, 2H). LCMS: RT 0.746 min, m/z=252.1 [M+H]⁺.

3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one

To a solution of3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one (780 mg,3.29 mmol) in THF (15 mL) was added LDA (4.93 mmol, 2 M, 2.47 mL) at−78° C. under N₂. The mixture was stirred at −78° C. for 30 min, thentreated with MeI (700 mg, 4.93 mmol, 307 μL) at −78° C. and warmed to 0°C. and stirred for 1.5 h. The mixture was poured into sat. NH₄Cl (15 mL)and extracted with EtOAc (3×5 mL). The combined organic phase was washedwith brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=1:0 to 1:1) to give3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one asa colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 7.27 (s, 1H),4.55 (td, J=8.53, 5.77 Hz, 1H), 4.38-4.48 (m, 1H), 3.12-3.22 (m, 1H),2.56-2.65 (m, 1H), 2.49 (ddd, J=13.49, 7.59, 5.90 Hz, 1H), 1.84 (s, 3H),1.00-1.09 (m, 2H), 0.90-1.00 (m, 3H). LCMS: RT 0.746 min, m/z=252.1[M+H]⁺.

3-(4-amino-3-cyclopropyl-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one

To a solution of3-(3-cyclopropyl-4-nitro-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one(555 mg, 2.21 mmol) in MeOH (15 mL) was added Pd—C (10%, 220 mg) underN₂. The suspension was degassed under reduced pressure and purged withH₂ for three times. The mixture was stirred under H₂ (15 psi) at 20° C.for 2 h. The mixture was filtered and the filtrate was concentratedunder reduced pressure to give3-(4-amino-3-cyclopropyl-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one asa yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.18 (s, 1H), 4.43-4.51 (m,1H), 4.30-4.39 (m, 1H), 3.25 (ddd, J=13.05, 7.53, 5.02 Hz, 1H), 2.91 (brs, 2H), 2.36 (dt, J=13.43, 7.47 Hz, 1H), 1.72 (s, 3H), 1.62-1.70 (m,1H), 0.82-0.90 (m, 2H), 0.79 (ddd, J=7.81, 4.99, 2.38 Hz, 2H).

(3S)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-3-methyl-tetrahydrofuran-2-oneand(3R)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]3-methyl-tetrahydrofuran-2-one

A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (143mg, 677.95 μmol) and3-(4-amino-3-cyclopropyl-pyrazol-1-yl)-3-methyl-tetrahydrofuran-2-one(150 mg, 677.95 μmol) in 1,4-dioxane (10 mL) was added p-TsOH.H₂O (40mg, 203.39 μmol at 20° C. under N₂ and stirred at 90° C. for 4 h. Themixture was poured into ice-water (10 mL) and extracted with EtOAc (3×8mL). The combined organic phase was washed with brine (8 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC (SiO₂, PE:EtOAc=1:1) to give3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-3-methyl-tetrahydrofuran-2-one.The enantiomers were separated by SFC to provide(3S)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]3-methyl-tetrahydrofuran-2-oneand(3R)-3-[3-cyclopropyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]-3-methyl-tetrahydrofuran-2-one.

First Eluting Isomer—

¹H NMR (400 MHz, CDCl₃): δ 8.28 (br s, 1H), 8.13 (br s, 1H), 7.08 (br s,1H), 5.25 (br s, 1H), 4.47 (br d, J=7.53 Hz, 1H), 4.38 (td, J=8.38, 4.83Hz, 1H), 3.31 (br s, 1H), 3.11 (br s, 3H), 2.43 (dt, J=13.52, 7.48 Hz,1H), 1.78 (s, 3H), 1.67-1.75 (m, 1H), 0.77-0.95 (m, 4H). HPLC: RT: 2.00min. MS: m/z=397.2 [M+H]⁺.

Second Eluting Isomer—

¹H NMR (400 MHz, CDCl₃): δ 8.28 (br s, 1H), 8.13 (br s, 1H), 7.08 (br s,1H), 5.25 (br s, 1H), 4.47 (br d, J=7.40 Hz, 1H), 4.33-4.42 (m, 1H),3.32 (br s, 1H), 3.11 (br s, 3H), 2.37-2.49 (m, 1H), 1.78 (s, 3H),1.67-1.76 (m, 1H), 0.79-0.94 (m, 4H). HPLC: RT: 2.00 min. MS: m/z=397.2[M+H]⁺.

Example 12 Synthesis of2-[4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-cyclopentanone(194) 2-(4-bromo-3-methyl-pyrazol-1-yl)cyclopentanone and2-(4-bromo-5-methyl-pyrazol-1-yl)cyclopentanone

To a solution of 4-bromo-3-methyl-1H-pyrazole (10 g, 62.11 mmol) in DMF(60 mL) was added NaH (3.23 g, 80.75 mmol, 60% purity) at 0° C. andstirred at 15° C. for 1 h. Then 2-chlorocyclopentanone (8.84 g, 74.53mmol, 7.43 mL) was added to the mixture and stirred at 15° C. for 15 h.The reaction mixture was quenched by addition aq. NH₄Cl (300 mL) at 0°C., and then extracted with EtOAc (3×100 mL). The combined organiclayers were washed with brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:MTBE=2:1 to 1:1) to give the mixture of2-(4-bromo-3-methyl-pyrazol-1-yl)cyclopentanone and2-(4-bromo-5-methyl-pyrazol-1-yl)cyclopentanone as a yellow gum. LCMS:RT 2.119 min, m/z=243.1 [M+H]⁺.

2-(4-bromo-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone and2-(4-bromo-5-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone

To a mixture of 2-(4-bromo-3-methyl-pyrazol-1-yl)cyclopentanone and2-(4-bromo-5-methyl-pyrazol-1-yl)cyclopentanone (6.5 g, 26.74 mmol) inTHF (30 mL) was added LiHMDS (1 M, 34.76 mL) and stirred at −78° C. for1 h. MeI (4.93 g, 34.76 mmol, 2.16 mL) was then added at −78° C. andstirred at 15° C. for 15 h. The reaction mixture was quenched byaddition of saturated aq. NH₄Cl (200 mL) at 0° C., and then extractedwith EtOAc (3×70 mL). The combined organic layers were washed with brine(100 mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=4:1 to 2:1) to give the mixture of2-(4-bromo-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone) and2-(4-bromo-5-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone as a yellowgum. LCMS: RT 0.747 min, m/z=257.1 [M+H]⁺.

tert-butylN-[3-methyl-1-(1-methyl-2-oxo-cyclopentyl)pyrazol-4-yl]carbamate andtert-butylN-[5-methyl-1-(1-methyl-2-oxo-cyclopentyl)pyrazol-4-yl]carbamate

A mixture of 2-(4-bromo-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanoneand 2-(4-bromo-5-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone (160 mg,622.26 μmol, NH₂Boc (437 mg, 3.73 mmol), t-BuONa (120 mg, 1.24 mmol) and[2-(2-aminoethyl)phenyl]-chloro-palladium;ditert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (107 mg,155.57 μmol in THF (2 mL) was degassed and purged with N₂ for 3 times,and then the mixture was stirred at 90° C. for 2 h under N₂. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by prep-HPLC (neutral) togive tert-butylN-[3-methyl-1-(1-methyl-2-oxo-cyclopentyl)pyrazol-4-yl]carbamate andtert-butylN-[5-methyl-1-(1-methyl-2-oxo-cyclopentyl)pyrazol-4-yl]carbamate as ayellow gum. LCMS: RT 1.203 min, m/z=294.3 [M+H]⁺.

2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone

A solution of tert-butylN-[3-methyl-1-(1-methyl-2-oxo-cyclopentyl)pyrazol-4-yl]carbamate (80 mg,272.7 μmol in HCl/EtOAc (3 mL) was stirred at 0° C. for 1 h. Thereaction mixture was concentrated under reduced pressure to give2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone as a yellowsolid. LCMS: RT 1.032 min, m/z=194.2 [M+H]⁺.

2-[4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-pyrazol-1-yl]-2-methyl-cyclopentanone

2-(4-amino-3-methyl-pyrazol-1-yl)-2-methyl-cyclopentanone (55 mg, 284.61μmol, 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (64 mg,284.61 μmol and TEA (86 mg, 853.84 μmol, 118.84 μL) were taken up into amicrowave tube in n-BuOH (1 mL). The sealed tube was heated at 110° C.for 1 h under microwave. The mixture was concentrated under reducedpressure. The residue was purified by prep-HPLC (neutral) and prep-TLC(PE:EtOAc=1:1) to give2-[4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]3-methyl-pyrazol-1-yl]2-methyl-cyclopentanone.¹H NMR (400 MHz, CHLOROFORM-d): δ ppm 8.12 (br s, 2H), 6.66 (br s, 1H),5.15 (br s, 1H), 3.58 (br s, 2H), 2.90-3.07 (m, 1H), 2.38-2.58 (m, 2H),2.24 (s, 3H), 2.04-2.19 (m, 2H), 1.88-2.00 (m, 1H), 1.58 (s, 3H), 1.31(br t, J=7.09 Hz, 3H). HPLC: Retention Time: 2.557 min. MS: (M+H⁺) m/z:383.2.

Example 13 Synthesis of(S)-3-(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-3-(fluoromethyl)dihydrofuran-2(3H)-oneand(R)-3-(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-3-(fluoromethyl)dihydrofuran-2(3H)-one(216 and 217)3-(hydroxymethyl)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one

To a mixture of 3-(3-methyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one(2 g, 9.47 mmol) in THF (25 mL) was added LiHMDS (1 M, 12.31 mL) at −78°C. under N₂, and then the mixture was stirred at −78° C. for 0.5 h. Asolution of paraformaldehyde (1.02 g, 11.37 mmol) in THF (1 mL) was thenadded to the reaction mixture and then the mixture was stirred at 10° C.for 2.5 h. The reaction was quenched by addition aq. sat. NH₄Cl (150 mL)at 0° C., and then extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (50 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (PE:EtOAc=2:1 to 1:1) to give3-(hydroxymethyl)-3-(3-methyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-oneas a white solid. LCMS: RT 0.497 min, m/z=242.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d): δ 8.54 (s, 1H), 4.59-4.48 (m, 2H), 4.20-4.07 (m, 2H),3.07-2.98 (m, 1H), 2.95-2.86 (m, 2H), 2.55 (s, 3H).

3-(fluoromethyl)-3-(3-methyl-4-nitro-1H-pyrazol-1-yl)dihydrofuran-2(3H)-one

To a solution of3-(hydroxymethyl)-3-(3-methyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one(1.1 g, 4.56 mmol) in DCM (30 mL) was added DAST (5.88 g, 36.48 mmol,4.82 mL) at 0° C., then the mixture was stirred at 20° C. for 15 h. Themixture was quenched by addition aq. sat. NaHCO₃ (200 mL) at 0° C., andextracted with EtOAc (3×70 mL). The combined organic layers were washedwith brine (70 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=3:1 to 1:1) to give3-(fluoromethyl)-3-(3-methyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-oneas a white solid. LCMS: RT 0.576 min, m/z=244.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d): δ 8.56 (s, 1H), 4.96-4.74 (m, 2H), 4.59-4.49 (m, 2H),3.30-3.20 (m, 1H), 2.95-2.86 (m, 1H), 2.55 (s, 3H).

3-(4-amino-3-methyl-1H-pyrazol-1-yl)-3-(fluoromethyl)dihydrofuran-2(3H)-one

A mixture of3-(fluoromethyl)-3-(3-methyl-4-nitro-pyrazol-1-yl)tetrahydrofuran-2-one(0.7 g, 2.88 mmol), Fe (804 mg, 14.39 mmol) and NH₄Cl (770 mg, 14.39mmol) in EtOH (8 mL) and H₂O (2 mL) was stirred at 70° C. for 2 h. Thereaction mixture was concentrated under reduced pressure, the residuewas diluted with DCM:MeOH (50 mL, ratio=10:1), filtered and concentratedunder reduced pressure to give3-(4-amino-3-methyl-pyrazol-1-yl)-3-(fluoromethyl)tetrahydrofuran-2-oneas a brown solid. LCMS: RT 0.087 min, m/z=214.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d): δ 7.30 (s, 1H), 4.89-4.66 (m, 2H), 4.52-4.40 (m, 2H),3.31 (br dd, J=6.2, 13.2 Hz, 1H), 2.87-2.80 (m, 1H), 2.21-2.15 (m, 3H).

(R)-3-(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-3-(fluoromethyl)dihydrofuran-2(3H)-oneand(S)-3-(4-((4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methyl-1H-pyrazol-1-yl)-3-(fluoromethyl)dihydrofuran-2(3H)-one

A mixture of3-(4-amino-3-methyl-pyrazol-1-yl)-3-(fluoromethyl)tetrahydrofuran-2-one(0.2 g, 938.05 μmol,2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (190 mg, 844.24μmol and p-TsOH.H₂O (71 mg, 375.22 μmol in 1,4-dioxane (3 mL) wasstirred at 90° C. for 6 h under N₂. The reaction mixture was quenched byaddition aq. sat. NaHCO₃ (60 mL) at 0° C., and then extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=3:1to 1:1) to give desired compound as a brown oil, which was separated bySFC.

SFC, First Eluting Isomer:

¹H NMR (400 MHz, CHLOROFORM-d): δ 8.30 (br s, 1H), 8.12 (s, 1H),7.01-6.61 (m, 1H), 5.32-5.06 (m, 1H), 4.91-4.68 (m, 2H), 4.54-4.37 (m,2H), 3.64-3.53 (m, 2H), 3.32 (br s, 1H), 2.92-2.79 (m, 1H), 2.26 (s,3H), 1.33 (br t, J=7.0 Hz, 3H). HPLC: Retention Time: 2.02 min. MS:(M+H⁺) m/z=403.3.

SFC, Second Eluting Isomer:

¹H NMR (400 MHz, CHLOROFORM-d): δ 8.30 (br s, 1H), 8.12 (s, 1H),7.01-6.61 (m, 1H), 5.32-5.06 (m, 1H), 4.91-4.68 (m, 2H), 4.54-4.37 (m,2H), 3.64-3.53 (m, 2H), 3.32 (br s, 1H), 2.92-2.79 (m, 1H), 2.26 (s,3H), 1.33 (br t, J=7.0 Hz, 3H). HPLC: Retention Time: 1.99 min. MS:(M+H⁺) m/z=403.3.

Example 14 Synthesis ofN2-[5-chloro-1-[(3S)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamineandN2-[5-chloro-1-[(3R)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4]N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine(204 and 205) tert-butyl3-(4-nitropyrazol-1-yl)-4-oxo-piperidine-1-carboxylate

To a solution of tert-butyl-3-bromo-4-oxo-piperidine-1-carboxylate (20g, 71.91 mmol) and 4-nitro-1H-pyrazole (8.94 g, 79.10 mmol) in DMF (100mL) was added K₂CO₃ (19.88 g, 143.81 mmol) at 20° C. under N₂. Themixture was stirred at 20° C. for 16 h. The mixture was poured intoice-water (300 mL) and extracted with EtOAc (3×100 mL). The combinedorganic phase was washed with brine (3×100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography (PE:EtOAc=1:0 to 3:1)to give tert-butyl3-(4-nitropyrazol-1-yl)-4-oxo-piperidine-1-carboxylate as a yellow oil.LCMS: RT 1.306 min, m/z=255.2 [M-56]⁺. ¹H NMR (400 MHz, CDCl₃): δ8.22-8.27 (m, 1H), 8.12 (s, 1H), 4.97 (dd, J=10.85, 6.34 Hz, 1H), 4.75(br s, 1H), 4.43 (br s, 1H), 3.64 (br t, J=11.86 Hz, 1H), 3.30 (br d,J=5.77 Hz, 1H), 1.41-1.58 (m, 9H), 1.41-1.58 (m, 2H).

tert-butyl 4,4-difluoro-3-(4-nitropyrazol-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl3-(4-nitropyrazol-1-yl)-4-oxo-piperidine-1-carboxylate (1 g, 3.22 mmol)in DCM (10 mL) was added DAST (2.6 g, 16.11 mmol, 2.13 mL) at −78° C.under N₂. The mixture was stirred at 20° C. for 16 h. The mixture waspoured into ice cold sat. NaHCO₃ (15 mL) and extracted with EtOAc (3×5mL). The combined organic phase was washed with brine (5 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=1:0to 3:1) to give tert-butyl4,4-difluoro-3-(4-nitropyrazol-1-yl)piperidine-1-carboxylate as a whitesolid. LCMS: RT 1.335 min, m/z=277.1 [M-56]⁺. ¹H NMR (400 MHz, CDCl₃): δ8.30 (s, 1H), 8.13 (s, 1H), 4.52 (ddq, J=14.23, 9.60, 4.65, 4.65, 4.65Hz, 1H), 4.39 (br s, 1H), 4.10 (br s, 1H), 3.66 (br t, J=11.36 Hz, 1H),3.30 (br t, J=11.42 Hz, 1H), 2.26-2.42 (m, 1H), 1.95-2.18 (m, 1H),1.37-1.57 (m, 9H).

tert-butyl3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine-1-carboxylate

To a solution of tert-butyl4,4-difluoro-3-(4-nitropyrazol-1-yl)piperidine-1-carboxylate (740 mg,2.23 mmol) in THF (10 mL) was added dropwise LiHMDS (1 M, 3.34 mmol,3.34 mL) at −78° C. under N₂. The reaction was stirred at −78° C. for 1h. Then 1,1,1,2,2,2-hexachloroethane (1.05 g, 4.45 mmol, 504.49 μL) inTHF (5 mL) was added dropwise and the mixture was stirred at −78° C. for1 h. The mixture was poured into sat. NH₄Cl (15 mL) and extracted withEtOAc (3×5 mL). The combined organic phase was washed with brine (5 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by silica gel column chromatography(PE:EtOAc=1:0 to 3:1) to give tert-butyl3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine-1-carboxylateas a yellow oil. LCMS: RT 1.352 min, m/z=311.2 [M-56]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.22 (s, 1H), 4.59-4.72 (m, 1H), 4.00-4.16 (m, 2H), 3.81-3.90(m, 1H), 3.55 (br d, J=9.03 Hz, 1H), 2.38-2.54 (m, 1H), 1.96-2.15 (m,1H), 1.39-1.56 (m, 9H).

3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine

The mixture of tert-butyl3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine-1-carboxylate(1.8 g, 4.91 mmol) in HCl/EtOAc (40 mL) was stirred at 20° C. for 2 h.The reaction mixture was concentrated under reduced pressure and themixture was adjusted to pH=7-8 with sat. aq. NaHCO₃. Then the aqueousphase was extracted with EtOAc (3×15 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to give3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine as a lightyellow solid. ¹H NMR (400 MHz, CHLOROFORM-d): δ 8.17-8.32 (m, 1H),4.57-4.81 (m, 1H), 3.59 (br dd, J=13.68, 4.89 Hz, 1H), 3.36 (br dd,J=13.93, 4.02 Hz, 1H), 3.14-3.27 (m, 1H), 2.98-3.11 (m, 1H), 2.37 (br s,1H), 2.14-2.34 (m, 1H).

3-(5-chloro-4-nitro-pyrazol-1-yl)-1-ethyl-4,4-difluoro-piperidine

To a mixture of3-(5-chloro-4-nitro-pyrazol-1-yl)-4,4-difluoro-piperidine (0.5 g) andacetaldehyde (2.07 g, 18.75 mmol, 2.63 mL) in MeOH (10 mL) was addedNaBH₃CN (589 mg, 9.38 mmol) and stirred for 15 min. Then CH₃COOH (1.13g, 18.75 mmol, 1.07 mL) was added to the solution at 20° C. and themixture was stirred at 20° C. for 1 h. The mixture was adjusted topH=7-8 with sat. aq. NaHCO₃ and the aqueous phase was extracted withEtOAc (3×15 mL). The combined organic phase was washed with brine (10mL), dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (PE:EtOAc=100:1 to 0:1) to give3-(5-chloro-4-nitro-pyrazol-1-yl)-1-ethyl-4,4-difluoro-piperidine as ayellow oil. LCMS: RT 0.939 min, m/z=295.1 [M+H]⁺. ¹H NMR (400 MHz,CHLOROFORM-d) δ: 8.19-8.33 (m, 1H), 4.78-4.95 (m, 1H), 3.10-3.22 (m,2H), 2.97-3.06 (m, 1H), 2.57-2.67 (m, 2H), 2.39-2.51 (m, 1H), 2.22-2.36(m, 1H), 2.12-2.21 (m, 1H), 1.13 (t, J=7.22 Hz, 3H).

5-chloro-1-(1-ethyl-4,4-difluoro-3-piperidyl)pyrazol-4-amine

To a mixture of3-(5-chloro-4-nitro-pyrazol-1-yl)-1-ethyl-4,4-difluoro-piperidine (0.15g, 509.02 μmol in EtOH (4 mL) and H₂O (1 mL) was added Fe (142 mg, 2.55mmol) and NH₄Cl (136 mg, 2.55 mmol, 88.98 μL) at 20° C. Then the mixturewas stirred at 80° C. for 1 h. The reaction mixture was filtered and thefiltrate was concentrated under reduced pressure. The crude was washedwith DCM: MeOH (V:V=10:1) (30 mL), filtered and the filtrate wasconcentrated under reduced pressure to give5-chloro-1-(1-ethyl-4,4-difluoro-3-piperidyl)pyrazol-4-amine as a redsolid. LCMS: RT 1.150 min, m/z=265.1 [M+H]⁺.

N2-[5-chloro-1-[(3S)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamineandN2-[5-chloro-1-[(3R)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4-]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine

To a mixture of5-chloro-1-(1-ethyl-4,4-difluoro-3-piperidyl)pyrazol-4-amine (0.13 g,491.12 μmol and 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine(110 mg, 491.12 μmol in 1,4-dioxane (3 mL) was added p-TsOH.H₂O (25 mg,147.33 μmol at 20° C. and the mixture was stirred at 90° C. for 5 h. Themixture was adjusted to pH=7-8 with sat. aq. NaHCO₃ and the aqueousphase was extracted with EtOAc (3×5 mL). The combined organic phase waswashed with brine (8 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (SiO₂, EtOAc) to give desired compound as a white syrup, whichwas further separated by SFC to giveN2-[5-chloro-1-[(3S)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamineas a white syrup andN2-[5-chloro-1-[(3R)-1-ethyl-4,4-difluoro-3-piperidyl]pyrazol-4-yl]-N4-ethyl-5-(trifluoromethyl)pyrimidine-2,4-diamine.

SFC, First Eluting Isomer:

¹H NMR (400 MHz, CHLOROFORM-d): δ 8.23 (br s, 1H), 8.13 (s, 1H), 6.72(br s, 1H), 5.14 (br s, 1H), 4.64-4.79 (m, 1H), 3.48-3.64 (m, 2H), 3.14(br d, J=8.41 Hz, 2H), 2.99 (br d, J=10.67 Hz, 1H), 2.60 (q, J=7.15 Hz,2H), 2.35-2.50 (m, 1H), 2.04-2.34 (m, 2H), 1.27 (t, J=7.22 Hz, 3H), 1.13(t, J=7.15 Hz, 3H). HPLC: RT: 1.116 min MS: m/z=454.4 [M+H]⁺. SFC:Retention Time: 1.621 min.

SFC, Second Eluting Isomer:

¹H NMR (400 MHz, CHLOROFORM-d): δ 8.23 (br s, 1H), 8.14 (s, 1H), 6.71(br s, 1H), 5.13 (br s, 1H), 4.60-4.81 (m, 1H), 3.49-3.61 (m, 2H), 3.15(br d, J=8.28 Hz, 2H), 2.99 (br d, J=11.80 Hz, 1H), 2.60 (q, J=7.15 Hz,2H), 2.43 (br t, J=12.05 Hz, 1H), 2.06-2.33 (m, 2H), 1.27 (t, J=7.22 Hz,3H), 1.13 (t, J=7.15 Hz, 3H). HPLC: Retention Time: 1.108 min. MS:m/z=454.4 [M+H]⁺. SFC: Retention Time: 1.785 min.

Example 15 Synthesis of(1S,2R)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitrileand(1R,2S)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitrile(213 and 214) 3-cyclopropyl-4-nitro-1-vinyl-pyrazole

To a mixture of 3-cyclopropyl-4-nitro-1H-pyrazole (7 g, 45.71 mmol) andbenzyl triethyl ammonium chloride (1.04 g, 4.57 mmol) in1,2-dichloroethane (50 mL) was added NaOH (9.14 g, 228.55 mmol) andwater (9 mL) at 20° C. under N₂. The mixture was stirred at 80° C. for 8h. The reaction mixture was filtered and the filtrate was concentrated.The crude product was purified by silica gel column chromatography(PE:EtOAc=100:1 to 1:1) to give 3-cyclopropyl-4-nitro-1-vinyl-pyrazoleas a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ ppm 8.23 (s, 1H), 6.87 (dd, J=15.55, 8.71 Hz,1H), 5.70, (d, J=15.66 Hz, 1H), 5.06 (d, J=8.60 Hz, 1H), 2.53-2.68 (m,1H), 0.97-1.11 (m, 4H).

Ethyl(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylateand ethyl(1S,2S)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylate

To a mixture of 3-cyclopropyl-4-nitro-1-vinyl-pyrazole (4.7 g, 26.23mmol) and 3-[3-(2-carboxy-2-methyl-propyl)phenyl]-2,2-dimethyl-propanoicacid; rhodiorhodium (200 mg, 262.31 μmol in DCM (100 mL) was addeddropwise ethyl 2-diazoacetate (17.96 g, 157.39 mmol) in DCM (30 mL) at20° C. under N₂ for 3 h. The mixture was stirred at 20° C. for 12 h. Themixture was concentrated. The residue was purified by silica gel columnchromatography (PE:EtOAc=100:1 to 1:1) to give ethyl(1S*,2R*)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylateand ethyl(1S*,2S*)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylateas a brown oil.

(1S*,2R*)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylate

¹H NMR (400 MHz, CDCl₃): δ 8.15 (s, 1H), 4.12-4.37 (m, 1H), 3.97-4.07(m, 2H), 3.90 (td, J=7.50, 5.71 Hz, 1H), 2.43-2.71 (m, 1H), 2.13-2.37(m, 1H), 1.88-2.07 (m, 1H), 1.59 (td, J=8.06, 6.46 Hz, 1H), 1.23-1.36(m, 1H), 1.17 (t, J=7.15 Hz, 3H), 0.84-1.06 (m, 4H).

(1S*,2S*)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylate

¹H NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 4.08-4.32 (m, 3H), 3.98 (ddd,J=7.97, 4.89, 3.07 Hz, 1H), 2.50-2.65 (m, 1H), 2.30 (ddd, J=9.54, 6.27,3.01 Hz, 1H), 1.79 (dt, J=9.91, 5.21 Hz, 1H), 1.65 (dt, J=8.03, 5.96 Hz,1H), 1.24-1.36 (m, 4H), 0.92-1.10 (m, 4H).

(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylicacid

To a mixture of ethyl(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylate(2.2 g, 8.29 mmol) in 1,4-dioxane (20 mL) was added HCl (2 M, 20 mL) at20° C. under N₂. The mixture was stirred at 60° C. for 12 h. The mixturewas concentrated to give(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylicacid as a brown solid. ¹H NMR (400 MHz, DMSO): δ 8.84 (s, 1H), 4.01-4.10(m, 1H), 2.39-2.46 (m, 1H), 2.02-2.10 (m, 1H), 1.98 (q, J=6.03 Hz, 1H),1.46-1.55 (m, 1H), 0.93-1.07 (m, 2H), 0.76-0.89 (m, 2H).

(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxamide

To a mixture of(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxylicacid (2 g, 8.43 mmol), NH₄Cl (2.71 g, 50.59 mmol) and DIPEA (6.54 g,50.59 mmol) in DMF (20 mL) was added HATU (6.41 g, 16.86 mmol) at 20° C.under N₂. The mixture was stirred at 20° C. for 4 h. The mixture waspoured into ice-water (100 mL). The aqueous phase was extracted withEtOAc (3×50 mL). The combined organic phase was washed with brine (3×50mL), dried with anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to give(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxamideasa brown solid. ¹H NMR (400 MHz, DMSO): δ 8.67 (s, 1H), 7.65 (br s, 1H),6.87 (br s, 1H), 3.81-3.98 (m, 1H), 2.38-2.47 (m, 1H), 2.04 (q, J=7.57Hz, 1H), 1.93 (q, J=5.73 Hz, 1H), 1.37 (td, J=8.05, 5.95 Hz, 1H),1.21-1.29 (m, 1H), 0.94-1.01 (m, 2H), 0.78-0.84 (m, 1H).

(1S, 2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl) cyclopropanecarbonitrile

To a mixture of (1S, 2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarboxamide (1.7 g, 7.2 mmol) in EtOAc (80 mL) was added T3P(18.32 g, 28.79 mmol, 17.12 mL, 50% purity) at 20° C. under N₂. Themixture was stirred at 75° C. for 12 h. The mixture was poured into aq.NaHCO₃ (200 mL). The aqueous phase was extracted with EtOAc (3×50 mL).The combined organic phase was washed with brine (150 mL), dried withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography (PE:EtOAc=100:1to 1:1) to give(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarbonitrileas a white solid. LCMS: RT 1.20 min, m/z=219.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): δ 8.26 (s, 1H), 3.90-4.09 (m, 1H), 2.62 (tt, J=8.05, 5.29 Hz,1H), 2.10-2.20 (m, 1H), 2.01 (dt, J=9.43, 6.64 Hz, 1H), 1.75 (dt,J=9.26, 7.39 Hz, 1H), 1.00-1.11 (m, 4H).

(1S, 2R)-2-(4-amino-3-cyclopropyl-pyrazol-1-yl)cyclopropanecarbonitrile

To a mixture of(1S,2R)-2-(3-cyclopropyl-4-nitro-pyrazol-1-yl)cyclopropanecarbonitrile(0.8 g, 3.67 mmol) and Fe (1.02 g, 18.33 mmol) in EtOH (20 mL) and water(5 mL) was added NH₄Cl (981 mg, 18.33 mmol) at 20° C. under N₂. Themixture was stirred at 75° C. for 1 h. The mixture was filtered and thefiltrate was concentrated. The residue was washed with DCM: MeOH (10:1,3×10 mL), filtered and the filtrate was concentrated under reducedpressure to give (1S, 2R)-2-(4-amino-3-cyclopropyl-pyrazol-1-yl)cyclopropanecarbonitrile (0.75 g, crude) as a brown oil. LCMS: RT 0.81min, m/z=189.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): δ 6.97-7.15 (m, 1H),3.74-3.91 (m, 1H), 2.03 (q, J=6.25 Hz, 1H), 1.80 (dt, J=9.43, 6.42 Hz,1H), 1.64-1.74 (m, 1H), 1.54-1.63 (m, 1H), 0.78-0.93 (m, 4H).

(1S,2R)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitrileand(1R,2S)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitrile

To a mixture of(1S,2R)-2-(4-amino-3-cyclopropyl-pyrazol-1-yl)cyclopropanecarbonitrile(0.1 g, 531.27 μmol and 5-bromo-2-chloro-4-methoxy-pyrimidine (119 mg,531.27 μmol in 1,4-dioxane (2 mL) was added p-TsOH.H₂O (30 mg, 159.38μmol at 20° C. under N₂. The mixture was stirred at 85° C. for 4 h. Themixture was poured into aq. NaHCO₃ (5 mL) and extracted with EtOAc (3×5mL). The combined organic phase was washed with brine (10 mL), driedwith anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(PE:EtOAc=100:1 to 1:1) and separated by SFC to give(1S,2R)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitrileand(1R,2S)-2-[4-[(5-bromo-4-methoxy-pyrimidin-2-yl)amino]-3-cyclopropyl-pyrazol-1-yl]cyclopropanecarbonitriles.

SFC, First Eluting Isomer:

¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 8.01 (s, 1H), 6.76 (br s, 1H),4.05 (s, 3H), 3.85-3.97 (m, 1H), 2.11 (q, J=6.27 Hz, 1H), 1.88 (dt,J=9.29, 6.46 Hz, 1H), 1.60-1.78 (m, 2H), 0.84-0.97 (m, 4H). LCMS:reaction time: 1.475 min. MS: [M+H]⁺ m/z: 375.2.

SFC, First Eluting Isomer:

¹H NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 8.01 (s, 1H), 6.77 (br s, 1H),4.05 (s, 3H), 3.86-3.96 (m, 1H), 2.11 (q, J=6.27 Hz, 1H), 1.88 (dt,J=9.29, 6.53 Hz, 1H), 1.61-1.77 (m, 2H), 0.85-0.97 (m, 4H). LCMS:reaction time: 1.465 min. MS: [M+H]⁺ m/z: 375.2.

The other compounds of Table 1A, 1B, 2A and 2B were, or can be, preparedaccording to the Examples above and/or general procedures describedherein using the appropriate starting materials.

Example 16 Biochemical Assay of the Compounds

Materials:

-   -   LRRK2 G2019S enzyme    -   Substrate (LRRKtide)    -   ATP    -   TR-FRET dilution buffer    -   pLRRKtide antibody    -   384-well assay plate    -   DMSO

Enzyme Reaction Conditions

-   -   50 mM Tris pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.01% Brij-35, 2 mM        DTT    -   5 nM LRRK2    -   134 μM ATP    -   60 minute reaction time    -   23° C. reaction temperature    -   10 μL total reaction volume

Detection Reaction Conditions

-   -   1× TR-FRET dilution buffer    -   10 mM EDTA    -   2 nM antibody    -   23° C. reaction temperature    -   10 μL total reaction volume

Compounds were prepared by initially diluting to 1 mM with DMSO. 35 μLof reference compound solution, 35 μL of test compound solution, and 35μL HPE were successively added to the source plate (384-well assayplate, Labcyte). The plates were centrifuged at 2500 rpm for 1 minuteand sealed in foil. POD was used to perform a 3.162 fold serial dilutionand 100 nL of reference compound solution, test compound solution, HPEand ZPE were transferred to assay plates. The assay plate wascentrifuged at 2500 rpm for 1 minute, and sealed with foil.

To perform the enzyme reaction, 5 μL of LRRKtide substrate and kinasemixture in assay buffer was added to all wells of the assay plate. Theplate was centrifuged to concentrate the mixture at the bottom of thewells. The assay plate was incubated at 23° C. for 20 minutes. Followingincubation, 5 μL of 2× ATP in assay buffer was added to each well, andplates were centrifuged to concentrate the mixture at the bottom of thewells. The plate was incubated at 23° C. for 60 minutes.

To perform the detection of the reaction, EDTA completely mixed inTR-FRET dilution buffer was added to antibody reagent. 10 μL ofdetection reagent was added to all wells of each well of the assay plateand the plate was centrifuged to concentrate the mixture at the bottomof the wells. The plate was then incubated at 23° C. for 60 minutes.Plates were read on Perkin Elmer Envision 2104 instrument in TR-FRETmode using a 340 nm excitation filter, 520 nm fluorescence emissionfilter, and 490 or 495 nm terbium emission filter.

Several of the compounds disclosed herein were tested according to theabove methods and found to exhibit an LRRK2 G2019S IC₅₀ as indicated inTable 3. In the table below, activity is provided as follows: +++=IC₅₀less than 30 nM; ++=IC₅₀ between 30 nM and 60 nM; +=IC₅₀ greater than 60nM.

TABLE 3 LRRK2 MS No. TR-FRET IC₅₀ (nM) [M + 1]+  1 +++ 396.2  2 + 396.3 3 +++ 353.1  4 +++ 353.1  5 +++ 392.1  6 + 378.1  7 +++ 378.1  8 +++325.1  9 +++ 409    10 + 409.1  11 +++ 389.1  12 +++ 389.1  13 +++ 389.1 14 +++ 396.2  15 +++ 395.2  16 +++ 341.2  17 +++ 341.1  18 +++ 409.2 19 +++ 350.2  20 +++ 355.2  21 +++ 378.1  22 +++ 404.2  23 +++ 404.3 24 +++ 404.2  25 +++ 387.3  26 +++ 366.2  27 +++ 366.1  28 +++ 468.2 29 +++ 468.2  30 ++ 371.2  31 ++ 371.2  32 +++ 352.1  33 +++ 410.1  34+++ 399.2  35A +++ 366.2  35B +++ 366.2  37 +++ 349.0  38 +++ 366.1  39A+++ 384.2  40 +++ 352.2  41 +++ 352.1  42 +++ 350.1  43 +++ 364.1  44+++ 363.3  45 +++ 349.2  46 +++ 399.2  48 +++ 375.2  50 +++ 331.1  52A+++ 338.1  52B +++ 338.2  54A +++ 380.2  54B +++ 380.1  57 +++ 396.2  58+++ 362.1  59 +++ 390.2  60 +++ 333.1  61 +++ 380.2  62 +++ 343.2  63+++ 346.1  64A +++ 381.1  64B +++ 381.1  65 +++ 381.1  66 +++ 376.1  67+++ 343.2  68 +++ 411.3  69 +++ 408.2  70 +++ 398.2  71 +++ 410.2  72+++ 332.1  73 +++ 400.1  74 +++ 368.3  75 +++ 409.1  76 +++ 404.1  77+++ 408.2  78 +++ 422.3  79 +++ 421.1  80 +++ 346.2  81 +++ 423.0  82+++ 399.2  83 +++ 399.2  84 +++ 380.2  85 +++ 413.1  86 +++ 424.3  87+++ 354.2  88 +++ 415.2  89 +++ 359.2  90 +++ 382.1, 384.0  91 +++ 374.3 92 +++ 434.4  93 +++ 390.1, 392.1  94 +++ 394.2  95 +++ 390.1, 392.1 96 +++ 429.1  97 +++ 434.2  98 +++ 385.1  99 +++ 391.3 100 +++ 385.2101 +++ 434.2 102 +++ 382.1, 384   103 +++ 382.2 104 +++ 411.2 105 +++391.2 106 +++ 489.3 107 +++ 378.3 108 +++ 411.2 109 +++ 273.2 110 +++ 417.25 111 +++ 401.1 112 +++ 391.1 113 +++ 397.2 114 +++ 423.1 115 +++423.1 116 +++ 434.4 117 +++ 405.3 118 +++ 380.2 119 +++ 371.2 120 +++382.2 121 +++ 489.3 122 +++ 397.2 123 +++ 391.2 124 +++ 371.2 125 +++385.2 126 +++ 433.8 127 +++ 436.3 128 +++ 419.2 129 +++ 410.2 130 +++384.2 131 +++ 380.2 132 +++ 391.1 133 + 338.1 134 +++ 371.2 135 + 355.2136 ++ 410.2 137 +++ 408.2 138 +++ 408.2 139 +++ 433.1 140 +++ 443.1,445.2 141 +++ 392.2 142 +++ 394.2 143 +++ 411.2 144 +++ 411.2 145 +++383.3 146 +++ 418.2, 420.2 147 +++ 418.2, 420.2 148 +++ 393.1 149 ++410.2 150 +++ 421.1, 423.1 151 +++ 421.1, 423.1 152 +++ 378.2 153 +++396.2 154 +++ 432.2 155 +++ 397.2 156 +++ 397.2 157 ++ 419.2, 421.2 158+++ 408.1 159 +++ 442.1, 444.1 160 ++ 408.2, 410.1 161 +++ 408.1, 410.1162 +++ 409   163 +++ 395.1 164 +++ 378.3 165 +++ 409.3 166 + 433.2 167+++ 433.2 168 +++ 395.2 169 +++ 425.3 170 +++ 396.3 171 + 434.3 172 +++434.3 173 +++ 388.2 174 +++ 388.3 175 +++ 374.2 176 +++ 374.3 177 +419.3 178 +++ 419.3 179 +++ 343.3 180 ++ 343.2 181 +++ 352.1 182 +++394.3 183 +++ 394.2 184 +++ 386.2 185 +++ 386.2 186 +++ 374.3 187 +++390.1, 392.1 188 ++ 394.2 189 ++ 394.2 190 +++ 345.1 191 +++ 385.3 192+++ 399.3 193 ++ 374.3 194 +++ 383.2 195 +++ 369.2 196 +++ 434.4 197 +++434.4 198 +++ 420.4 199 ++ 420.4 200 +++ 406.4 201 +++ 406.4 202 +++440.4 203 +++ 440.4 204 +++ 454.4 205 +++ 454.4 206 +++ 372.3 207 +++372.3 208 +++ 364.3 209 +++ 364.3 210 +++ 414.3 211 +++ 414.3 212 +++376.2 213 +++ 375.2 214 +++ 388.3 215 +++ 388.3 216 +++ 403.3 217 +++403.3 218 +++ 396.2

Example 17 Metabolic Stability

Metabolic stability of compounds was evaluated in human liver microsomes(from Corning or XenoTech, LLC) using a 96-well plate assay format.Compounds were incubated at 37° C. at 1 μM final concentration in themicrosomal matrix (0.5 mg/mL total protein) in the presence or absenceof NADPH cofactor. An NADPH regenerating system, comprised of NADP,MgCl₂, isocitric acid, and isocitrate dehydrogenase, was used in theassay. Enzymatic reactions were conducted for 0, 5, 10, 20, 30, or 60min before termination by addition of acetonitrile containingtolbutamide and labetalol internal standards (100 ng/mL). After shakingfor 10 min, plates were subjected to centrifugation (4000 rpm at 4° C.)for 20 min and supernatants were mixed 1:3 with HPLC grade water.Samples were analyzed by LC-MS/MS using appropriate MRM transitions foreach analyte and internal standard (IS). Analyte/IS peak area ratioswere used to determine percent compound remaining at each time point.Intrinsic clearance (Cl_(int); expressed as mL·min⁻¹·mg⁻¹) wascalculated from the first order elimination constant (k, min⁻¹) of testarticle decay and the volume of the incubation. These values were scaledto intrinsic organ clearance (Cl_(int)) using human specific scalingfactors (48.8 mg microsomal protein per g liver; 25.7 g liver per kgbody weight). Organ Cl_(int) was subsequently converted to hepaticclearance (CL_(hep), mL·min-1·kg-1) using the well-stirred model ofhepatic elimination, where Q_(h) is human hepatic blood flow (20.7mL·min-1·kg-1).

${CL}_{hep} = \frac{Q_{h}*{CL}_{int}}{\left( {Q_{h} + {CL}_{int}} \right)}$

CL_(hep) is the projected human clearance in the liver based on theabove in vitro assay. A lower value is indicative of less compound beingremoved by the liver. Surprisingly, compounds having a C5-pyrazoleattachment to the aminopyrimidine core resulted in a lower clearance(i.e., improved stability) as compared to compounds having a C4-pyrazoleattachment to the aminopyrimidine core, without a significant change inpotency.

TABLE 4 LRRK2 TR- Human liver Com- FRET microsomes pound IC₅₀ CL_(hep)No. Structure (nM) (mL/min/kg) 122

  (First eluting isomer) 0.72  9.856 155

  (First eluting isomer) 1.95  5.519 114

  (First eluting isomer) 1.05 16.508 150

  (First eluting isomer) 1.22 11.077 104

  (First eluting isomer) 0.96 11.59  143

  (First eluting isomer) 1.21 7.81  93

1.87 17.663 141

3.94 13.508 118

1.55 7.81 131

4.98  2.237

Example 18 MDR1-MDCK Permeability

The blood brain barrier (BBB) separates circulating blood from theextracellular fluid of the central nervous system (CNS). The passivemembrane permeability (Papp) and MDR1 (P-glycoprotein) substrate effluxpotential were determined using the MDR1-MDCK cell line as an in vitromodel of the effective permeability of a compound through the BBB. Abidirectional assay was conducted in pre-plated MDR1-MDCK cells using a12 or 96-well plate in the absence or presence of MDR1 inhibitor(GF120918 or Valspodar). Assays were run in duplicate in transportbuffer (HBSS, pH 7.4) for 90 or 120 min (minutes) at 37° C., using atest article concentration of 1 μM. Monolayer integrity was confirmedusing Lucifer yellow, and appropriate positive controls for passivepermeability and MDR1 transport were included in each experiment.Following incubation, samples from donor and receiver compartments wereremoved and quenched with acetonitrile containing an appropriateinternal standard (IS). Protein was precipitated by centrifugation for10 min at 3220 g, and supernatants were diluted in ultra-pure water (ifnecessary) prior to analysis by LC-MS/MS using appropriate MRMtransitions for analytes and IS. Papp (apparent permeability expressedin cm/sec [centimeter/second]) values were calculated according to thefollowing equation:

${P_{app}\mspace{14mu}\left( {{cm}\text{/}\sec} \right)} = {{\frac{{dC}_{R}}{dt} \times \frac{V_{R}}{\left( {{Area} \times C_{A}} \right)}}\mspace{14mu}{or}\mspace{14mu}{\frac{V_{R}}{{Area} \times {Time}} \times \frac{C_{R}}{C_{o}}}}$where V_(R) is the solution volume in the receiver chamber (apical orbasolateral side), Area is the surface area for the insert membrane),Time is incubation time expressed in seconds, C_(R) is the peak arearatio (analyte/IS) in the receiver chamber, C_(A) is the average of theinitial and final concentrations in the donor chamber, and C_(o) is theinitial peak area ratio in the donor chamber. P_(app) was determined inboth the apical to basolateral (A→B) and basolateral to apical (B→A)directions.

Monolayer efflux ratios (ER) were derived using the following equation:

${ER} = \left\lbrack \frac{P_{app}\left( {B->A} \right)}{P_{app}\left( {A->B} \right)} \right\rbrack$

Compounds with an MDR1-MDCK efflux ratio of less than or equal to fiveare likely to demonstrate ability to cross the blood-brain-barrier.

Compounds having the 1,2,3-triazole substituent were surprisingly brainpenetrant as compared to molecules having a 1,2,4-triazole moiety.

TABLE 5 Human liver LRRK2 microsomes Compound TR-FRET CL_(hep) MDR1 No.Structure IC₅₀ (nM) (mL/min/kg) ER 172

  (Second eluting isomer) 1.47 19.9  42    34

2.31 0.75 4.8  68

2.23 3.18  4.01  78

3.69 4.81 2    27

3.41 7.81  0.88 118

1.55 7.81  0.83 218

5.91 0   86.02

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The inventions illustratively described herein may suitably be practicedin the absence of any element or elements, limitation or limitations,not specifically disclosed herein. Thus, for example, the terms“comprising”, “including,” “containing”, etc. shall be read expansivelyand without limitation. Additionally, the terms and expressions employedherein have been used as terms of description and not of limitation, andthere is no intention in the use of such terms and expressions ofexcluding any equivalents of the features shown and described orportions thereof, but it is recognized that various modifications arepossible within the scope of the invention claimed.

Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification, improvement and variation of the inventionsembodied therein herein disclosed may be resorted to by those skilled inthe art, and that such modifications, improvements and variations areconsidered to be within the scope of this invention. The materials,methods, and examples provided here are representative of preferredembodiments, are exemplary, and are not intended as limitations on thescope of the invention.

The invention has been described broadly and generically herein. Each ofthe narrower species and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving any subject matter from the genus, regardless of whether or notthe excised material is specifically recited herein.

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group.

All publications, patent applications, patents, and other referencesmentioned herein are expressly incorporated by reference in theirentirety, to the same extent as if each were incorporated by referenceindividually. In case of conflict, the present specification, includingdefinitions, will control.

It is to be understood that while the disclosure has been described inconjunction with the above embodiments, that the foregoing descriptionand examples are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art to whichthe disclosure pertains.

The invention claimed is:
 1. A compound of formula Ia:

or a pharmaceutically acceptable salt, deuterated analog, prodrug,stereoisomer, or a mixture of stereoisomers thereof, wherein: R¹ isoptionally substituted cycloalkyl or C₁₋₆ alkyl optionally substitutedwith halo; R² is halo, cyano, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₆ alkenyl, optionally substituted C₂₋₆alkynyl, optionally substituted cycloalkyl, optionally substituted C₁₋₆alkoxy, optionally substituted cycloalkoxy, optionally substituted C₁₋₆alkylthio, optionally substituted C₁₋₆ alkylsulfonyl, —C(O)R¹⁰, or—C(O)N(R¹¹)(R¹²); R³ is optionally substituted C₁₋₆ alkoxy, optionallysubstituted cycloalkyl, optionally substituted cycloalkoxy, optionallysubstituted C₁₋₆ alkylthio, optionally substituted C₁₋₆ alkylsulfonyl,or —N(R¹¹)(R¹²); R⁴ is hydrogen or halo; R⁶ and R⁷ are eachindependently hydrogen or C₁₋₆ alkyl optionally substituted with halo;R⁸ and R⁹ are each independently hydrogen, cyano, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, oroptionally substituted heteroaryl; R¹⁰ is optionally substituted C₁₋₆alkyl or optionally substituted C₁₋₆ alkoxy; and R¹¹ and R¹² are eachindependently hydrogen, optionally substituted C₁₋₆ alkyl, or optionallysubstituted cycloalkyl.
 2. The compound of claim 1, wherein R⁶ and R⁷are methyl.
 3. The compound of claim 1, wherein at least one of R⁸ andR⁹ is hydrogen.
 4. The compound of claim 3, wherein both R⁸ and R⁹ arehydrogen.
 5. The compound of claim 1, wherein R¹ is optionallysubstituted cyclopropyl or optionally substituted cyclobutyl.
 6. Thecompound of claim 5, wherein R¹ is cyclopropyl independently substitutedwith one or more halo, hydroxy, cyano, or heteroaryl.
 7. The compound ofclaim 6, wherein R¹ is cyclopropyl, cyclobutyl, hydroxycyclobut-3-yl,cyanocyclobut-3-yl, triazol-2yl-cyclobut-3-yl,triazol-1-yl-cyclobut-3-yl, or fluorocyclobut-3-yl.
 8. The compound ofclaim 1, wherein R¹ is CD₃, ethyl, prop-2-yl, or methyl optionallysubstituted with halo.
 9. The compound of claim 1, wherein R² is halo,cyano, or C₁₋₆ alkyl optionally substituted with one or more halo. 10.The compound of claim 9, wherein R² is bromo.
 11. The compound of claim9, wherein R² is —CF₃.
 12. The compound of claim 1, wherein R³ isoptionally substituted cycloalkyl, optionally substituted C₁₋₆alkoxy, or—N(R¹¹)(R¹²).
 13. The compound of claim 1, wherein R³ is cyclopropyl,methoxy, 1,1-difluoroethy-2-ylamino, cyclopropylamino, —NH(CH₃), or—NH(CH₂CH₃).
 14. The compound of claim 1, wherein R⁴ is hydrogen. 15.The compound of claim 1, wherein R¹ is cycloalkyl independentlysubstituted with one or more hydroxy, cyano, or heteroaryl; R² is haloor C₁₋₆ haloalkyl; R³ is —N(R¹¹)(R¹²) or C₁₋₆ alkoxy; and R⁴ is H. 16.The compound of claim 15, wherein R¹² is optionally substituted C₁₋₆alkyl.
 17. The compound of claim 15, wherein R¹¹ is H and R¹² is ethyl.18. A compound, or a pharmaceutically acceptable salt, deuteratedanalog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomersthereof, wherein the compound is selected from:


19. A compound, or a pharmaceutically acceptable salt, deuteratedanalog, prodrug, tautomer, stereoisomer, or a mixture of stereoisomersthereof, wherein the compound is selected from:


20. A pharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, deuterated analog, prodrug, tautomer,stereoisomer, or a mixture of stereoisomers thereof, and apharmaceutically acceptable carrier, diluent, or excipient.
 21. Acompound having the structure:

or a pharmaceutically acceptable salt thereof.
 22. A pharmaceuticalcomposition comprising the compound of claim 21 and a pharmaceuticallyacceptable excipient.
 23. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition comprising the compound of claim 23 and a pharmaceuticallyacceptable excipient.
 25. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising the compound of claim 25 and a pharmaceuticallyacceptable excipient.
 27. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 28. A pharmaceuticalcomposition comprising the compound of claim 27 and a pharmaceuticallyacceptable excipient.
 29. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 30. A pharmaceuticalcomposition comprising the compound of claim 29 and a pharmaceuticallyacceptable excipient.